Extended release pharmaceutical compositions of levetiracetam

ABSTRACT

This invention relates to novel extended release pharmaceutical compositions of levetiracetam and preparations and characterizations thereof. This invention further relates to using these extended release pharmaceutical compositions of levetiracetam for the treatment of cognitive impairment associated with central nervous system (CNS) disorders in a subject in need or at risk thereof.

This application claims priority and benefit from U.S. ProvisionalPatent Application 62/165,812, filed May 22, 2015, and U.S.Non-Provisional Patent Application 15/160,424, filed May 20, 2016, thecontents and disclosures of which are incorporated herein by referencein their entirety.

FIELD OF THE INVENTION

This invention relates to novel extended release pharmaceuticalcompositions of levetiracetam and preparations and characterizationsthereof. This invention further relates to using these extended releasepharmaceutical compositions of levetiracetam for the treatment ofcognitive impairment associated with central nervous system (CNS)disorders in a subject in need or at risk thereof.

BACKGROUND OF THE INVENTION

Cognitive ability may decline as a normal consequence of aging or as aconsequence of a CNS disorder.

For example, a significant population of elderly adults experiences adecline in cognitive ability that exceeds what is typical in normalaging. Such age-related loss of cognitive function is characterizedclinically by progressive loss of memory, cognition, reasoning, andjudgment. Mild Cognitive Impairment (MCI), Age-Associated MemoryImpairment (AAMI), Age-Related Cognitive Decline (ARCD) or similarclinical groupings are among those related to such age-related loss ofcognitive function. According to some estimates, there are more than 16million people with AAMI in the U.S. alone (Barker et al., 1995), andMCI is estimated to affect 5.5-7 million in the U.S. over the age of 65(Plassman et al., 2008).

Cognitive impairment is also associated with other central nervoussystem (CNS) disorders, such as dementia, Alzheimer's Disease(AD),prodromal AD, post traumatic stress disorder (PTSD), schizophrenia,bipolar disorder (e.g., mania), amyotrophic lateral sclerosis (ALS),cancer-therapy-related cognitive impairment, mental retardation,Parkinson's disease (PD), autism, compulsive behavior, and substanceaddiction.

There is, therefore, a need for effective treatment of cognitiveimpairment associated with central nervous system (CNS) disorders and toimprove cognitive function in patients diagnosed with, for example,age-related cognitive impairment, MCI, amnestic MCI, AAMI, ARCD,dementia, Alzheimer's Disease (AD), prodromal AD, post traumatic stressdisorder (PTSD), schizophrenia, bipolar disorder (e.g., mania),amyotrophic lateral sclerosis, cancer-therapy-related cognitiveimpairment, mental retardation, Parkinson's disease (PD), autism,compulsive behavior, and substance addiction, and similar centralnervous system (CNS) disorders associated with cognitive impairment orat risk of developing them.

Levetiracetam is a widely used antiepileptic drug. Its InternationalUnion of Pure and Applied Chemistry (IUPAC) name is(2S)-2-(2-oxopyrrolidin-1-yl) butanamide) and its chemical structure isshown in Formula I.

Levetiracetam is indicated as adjunctive therapy in the treatment ofpartial onset seizures, or myoclonic seizures, or primary generalizedtonic-clonic seizures. It is recommended that such treatments should beinitiated with a daily dose of 1000 mg/day. Additional dosing incrementsmay be given to a maximum recommended daily dose of 3000 mg.Levetiracetam is currently available as immediate and extended releaseformulations for oral administration. Extended release dosage form oflevetiracetam is available in strengths of 500 mg, 750 mg, and 1000 mgfor once daily usage. Immediate release dosage form of levetiracetam isavailable in strengths of 250 mg, 500 mg, 750 mg, and 1000 mg for twicedaily usage.

International Application Nos. PCT/US09/05647, PCT/US12/24556, andPCT/US14/29170 disclose that levetiracetam, when administered at a doselower than the therapeutic doses for treating epilepsy, can treatcognitive impairment associated with central nervous system (CNS)disorders in a subject in need or at risk thereof.

The currently commercially available extended release dosage forms oflevetiracetam comprise 500 mg, 750 mg, and 1000 mg of levetiracetam.Such extended release dosage forms are not suitable for treatingcognitive impairment. There is, therefore, a need for novel extendedrelease compositions of levetiracetam for treating cognitive impairment.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides an extended releasepharmaceutical composition comprising: a) 220 mg of levetiracetam; b)280 mg-350 mg of hydroxypropyl methylcellulose; c) 1.2 mg-1.4 mg ofcolloidal silicon dioxide; d) 92.8 mg-119.2 mg of silicifiedmicrocrystalline cellulose; and e) 6.0 mg-6.7 mg of magnesium stearate.In another aspect, the present invention provides an extended releasepharmaceutical composition comprising: a) 220 mg of levetiracetam; b)280 mg of hydroxypropyl methylcellulose; c) 1.2 mg of colloidal silicondioxide; d) 92.8 mg of silicified microcrystalline cellulose; and e) 6.0mg of magnesium stearate. In another aspect, the present inventionprovides an extended release pharmaceutical composition comprising: a)220 mg of levetiracetam; b) 347.5 mg of hydroxypropyl methylcellulose;c) 1.4 mg of colloidal silicon dioxide; d) 119.2 mg of silicifiedmicrocrystalline cellulose; and e) 6.7 mg of magnesium stearate. Incertain embodiments of these aspects of the invention, the hydroxypropylmethylcellulose is Methocel™ K15M CR or Methocel™ K100M Premium CR. Incertain embodiments of these aspects of the invention, the hydroxypropylmethylcellulose is Methocel™ K15M CR. In certain embodiments of theseaspects of the invention, the silicified microcrystalline cellulose isProSolv™ HD90.

In another aspect, the present invention provides an extended releasepharmaceutical composition comprising: a) 190 mg of levetiracetam; b)300 mg of hydroxypropyl methylcellulose; c) 1.2 mg of colloidal silicondioxide; d) 102.8 mg of silicified microcrystalline cellulose; and e) 6mg of magnesium stearate. In another aspect, the present inventionprovides an extended release pharmaceutical composition comprising: a)190 mg of levetiracetam; b) 300 mg of hydroxypropyl methylcellulose; c)1.2 mg of colloidal silicon dioxide; d) 102.8 mg of anhydrous dicalciumphosphate; and e) 6 mg of magnesium stearate. In certain embodiments ofthese aspects of the invention, the hydroxypropyl methylcellulose isMethocel™ K15M CR or Methocel™ K100M Premium CR. In certain embodimentsof these aspects of the invention, the hydroxypropyl methylcellulose isMethocel™ K15M CR. In certain embodiments of these aspects of theinvention, the silicified microcrystalline cellulose is ProSolv™ HD90.

In certain embodiments of the invention, the extended releasepharmaceutical composition of the invention is formulated for once dailyadministration.

In certain embodiments of the invention, the extended releasepharmaceutical composition of the invention is formulated forone-unit-dosage-form-once-daily administration.

In certain embodiments of the invention, the extended releasepharmaceutical composition of the invention is in the form of a tablet.In some embodiments, the extended release pharmaceutical composition ofthe invention is in a tablet form and is formulated forone-tablet-once-daily administration.

In certain embodiments of the invention, the extended releasepharmaceutical composition of the invention is formulated for oraladministration.

In certain embodiments of the invention, the extended releasepharmaceutical composition of the invention does not comprise ahydrophobic rate controlling polymer.

In certain embodiments of the invention, the extended releasepharmaceutical composition of the invention does not comprise afunctional coating.

In another aspect, this invention provides methods of improvingcognition in a subject suffering from cognitive impairment or at riskthereof by administering the extended release pharmaceuticalcompositions of the invention. In certain embodiments, the subjectsuffers from cognitive impairment associated with a central nervoussystem (CNS) disorder, or at risk thereof. In certain embodiments, thecognitive impairment is associated with age-related cognitiveimpairment. In certain embodiments, the age-related cognitive impairmentis Mild Cognitive Impairment. In certain embodiments, the Mild CognitiveImpairment is amnestic Mild Cognitive Impairment. In certainembodiments, the cognitive impairment is associated with dementia,Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis, posttraumatic stress disorder, cancer therapy, bipolar disorder mentalretardation, Parkinson's disease, autism, compulsive behavior, orsubstance addiction.

In another aspect, this invention provides methods of treating mildcognitive impairment due to Alzheimer's disease in a human subject inneed thereof by administering the extended release pharmaceuticalcompositions of the invention.

In another aspect, this invention provides methods of treating amnesticmild cognitive impairment due to Alzheimer's disease in a human subjectin need thereof by administering the extended release pharmaceuticalcompositions of the invention.

In another aspect, this invention provides methods of slowing theprogression of mild cognitive impairment due to Alzheimer's disease in ahuman subject in need thereof by administering the extended releasepharmaceutical compositions of the invention.

In another aspect, this invention provides methods of slowing theprogression of amnestic mild cognitive impairment due to Alzheimer'sdisease in a human subject in need thereof by administering the extendedrelease pharmaceutical compositions of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow diagram of one embodiment of a process formanufacturing extended release compositions of levetiracetam (e.g., 190mg and 220 mg tablets listed in Tables 1 and 3).

FIG. 2 shows the mean concentrations of different levetiracetamformulations in plasma following oral administration to male dogs. Thetested levetiracetam formulations are: an immediate release 250 mglevetiracetam (LEV-IR) tablet being administered as 250 mg oral BID(twice daily) regimen (total dose of 500 mg); an extended release 500 mglevetiracetam tablet (LEV-XR) being administered as a single oral doseof 500 mg; the 190 mg Tablets A, B, and C of Table 1 being administeredas single oral doses of 190 mg. Plasma pharmacokinetic samples arecollected at pre-dose (i.e., 0), 0.25, 0.5, 1, 2, 4, 6, 8, 12, 13(LEV-IR 250 mg BID only), 18, 24, and 48 hours post dose. For LEV-IR 250mg BID, the 12-hour blood sample is collected just prior toadministration of the second dose.

FIG. 3 shows the mean concentrations of different levetiracetamformulations in plasma following oral administration to male dogs. Thetested levetiracetam formulations are: an extended release 500 mglevetiracetam tablet (LEV-XR) being administered as a single oral doseof 500 mg; the 220 mg Tablets D and E of Table 3 being administered assingle oral doses of 220 mg.

FIG. 4 shows the mean levetiracetam concentration-time profiles afteradministration of the 190 mg Tablet A of Table 1 under Fasted Conditions(Group 1/Treatment A: A1) and the 190 mg Tablet A of Table 1 under FedConditions (Group 1/Treatment B: B1).

FIG. 5 shows the mean levetiracetam concentration-time profiles afteradministration of the 220 mg Tablet D of Table 3 under Fasted Conditions(Group 2/Treatment A: A2) and the 220 mg Tablet D of Table 3 under FedConditions (Group 2/Treatment B: B2).

FIG. 6 shows the effective plasma level ranges based on Aged-Impairedrat studies and phase II study in aMCI patients. The acceptable rangegoal for the Phase I food effect study of the extended releaseformulations is established based on the effective plasma level range inaged-impaired rats and in aMCI patients, i.e., between 1.9 and 4.4μg/ml. The preferred range goal for the Phase I food effect study of theextended release formulations is established based on the effectiveplasma level range in aMCI patients, i.e., between 2.9 and 4.4 μg/ml.

FIG. 7 shows the steady state modeling of the PK profile of the 190 mgTablet A of Table 1, indicating that this tablet meets the acceptablerange goal, i.e., between 1.9 and 4.4 μg/ml.

FIG. 8 shows the steady state modeling of the PK profile of the 220 mgTablet D of Table 3, indicating that this tablet meets the preferredrange goal, i.e., between 2.9 and 4.4 μg/ml.

FIG. 9 is a flow diagram of another embodiment of a process formanufacturing extended release compositions of levetiracetam (e.g., 190mg and 220 mg tablets listed in Tables 1 and 3).

DETAILED DESCRIPTION OF THE INVENTION

This invention provides novel extended release pharmaceuticalcompositions of levetiracetam. This invention also provides methods ofusing these extended release pharmaceutical compositions oflevetiracetam for treating cognitive impairment or improving cognitivefunction associated with central nervous system (CNS) disorders in asubject in need or at risk thereof. This invention also provides usingthese extended release pharmaceutical compositions of levetiracetam inthe manufacture of medicaments for treating cognitive impairment orimproving cognitive function associated with central nervous system(CNS) disorders in a subject in need or at risk thereof.

In order that the invention herein described may be fully understood,the following details description is set forth.

Unless otherwise defined herein, scientific and technical terms used inthis application shall have the meanings that are commonly understood bythose of ordinary skill in the art to which this invention belongs.Generally, nomenclature used in connection with, and techniques of, celland tissue culture, molecular biology, cell biology, cancer biology,neurobiology, neurochemistry, virology, immunology, microbiology,genetics, protein and nucleic acid chemistry, chemistry, andpharmacology described herein, are those well known and commonly used inthe art. Each embodiment of the inventions described herein may be takenalone or in combination with one or more other embodiments of theinventions.

The methods and techniques of the present invention are generallyperformed, unless otherwise indicated, according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout thisspecification. See, e.g. “Principles of Neural Science”, McGraw-HillMedical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”,Oxford University Press, Inc. (1995); Lodish et al., “Molecular CellBiology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths etal., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co.,N.Y. (1999); Gilbert et al., “Developmental Biology, 6th ed.”, SinauerAssociates, Inc., Sunderland, Mass. (2000).

Chemistry terms used herein are used according to conventional usage inthe art, as exemplified by “The McGraw-Hill Dictionary of ChemicalTerms”, Parker S., Ed., McGraw-Hill, San Francisco, Calif. (1985).

All of the above, and any other publications, patents and publishedpatent applications referred to in this application are specificallyincorporated by reference herein. In case of conflict, the presentspecification, including its specific definitions, will control.

Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising” will be understood to imply the inclusion ofa stated integer (or components) or group of integers (or components),but not the exclusion of any other integer (or components) or group ofintegers (or components).

The singular forms “a,” “an,” and “the” include the plurals unless thecontext clearly dictates otherwise.

The term “including” is used to mean “including but not limited to”.“Including” and “including but not limited to” are used interchangeably.

In order to further define the invention, the following terms anddefinitions are provided herein.

Definitions

The term “extended release”, ““extended release form”, or “extendedrelease dosage form” is widely recognized in the art of pharmaceuticalsciences as systems that maintains therapeutic blood or plasma or tissuelevels of a drug for an extended period. An extended release dosage formpotentially provides greater effectiveness in the treatment of chronicdiseases or conditions; greater convenience; reduces side effects andprovides higher levels of patient compliance or therapeutic performancedue to a simplified dosage schedule, compared with those ofimmediate-release drugs. Extended release pharmaceutical products areformulated to release the active ingredient gradually and predictablyover an extended time period, such as a 24-hour period.

The term “extended release”, “extended release form”, or “extendedrelease dosage form” is used herein to refer to a controlled release oflevetiracetam from a dosage form to an environment over (throughout orduring) an extended period of time, e.g., twenty-four hours. An extendedrelease dosage form will release drug at substantially constant rateover an extended period of time or a substantially constant amount ofdrug will be released incrementally over an extended period of time. Theterm “extended release” used herein includes the terms “controlledrelease”, “prolonged release”, “sustained release”, “slow release”, or“modified release” as these terms are used in the pharmaceuticalsciences.

The term “active ingredient” “active pharmaceutical ingredient” or “API”as used herein is defined as a substance which has a therapeutic effect,such as levetiracetam.

A “patient”, “subject”, or “individual” are used interchangeably andrefer to either a human or a non-human animal. These terms includemammals, such as humans, primates, livestock animals (including bovines,porcines, etc.), companion animals (e.g., canines, felines, etc.) androdents (e.g., mice and rats).

“Cognitive function” or “cognitive status” refers to any higher orderintellectual brain process or brain state, respectively, involved inlearning and/or memory including, but not limited to, attention,information acquisition, information processing, working memory,short-term memory, long-term memory, anterograde memory, retrogradememory, memory retrieval, discrimination learning, decision-making,inhibitory response control, attentional set-shifting, delayedreinforcement learning, reversal learning, the temporal integration ofvoluntary behavior, and expressing an interest in one's surroundings andself-care, speed of processing, reasoning and problem solving and socialcognition.

In humans, cognitive function may be measured, for example and withoutlimitation, by measuring neuronal injury, measuring change in EntorhinalCortex thickness using structural Mill (e.g., for measuring neuronalinjury); the clinical global impression of change scale (CIBIC-plusscale); the Mini Mental State Exam (MMSE); the NeuropsychiatricInventory (NPI); the Clinical Dementia Rating Scale (CDR) (global,memory box); the Cambridge Neuropsychological Test Automated Battery(CANTAB); the Sandoz Clinical Assessment-Geriatric (SCAG); the BuschkeSelective Reminding Test (Buschke and Fuld, 1974); the Verbal PairedAssociates subtest; the Logical Memory subtest; the Visual Reproductionsubtest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997);the Benton Visual Retention Test; or the explicit 3-alternative forcedchoice task; or MATRICS consensus neuropsychological test battery; orADAS-Cog 13 item-scale; Wechsler Logical Memory I and II; BSP-O;Neuropsychological tests (Trails A and B, BNT, SR, CFT, R-O,Paired-associates), other MRI measures, DTI, resting fMRI, and the GDS.See Folstein et al., J Psychiatric Res 12: 189-98, (1975); Robbins etal., Dementia 5: 266-81, (1994); Rey, L'examen clinique en psychologie,(1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999);Marquis et al., 2002 and Masur et al., 1994. Also see Buchanan, R. W.,Keefe, R. S. E., Umbricht, D., Green, M. F., Laughren, T., and Marder,S. R. (2011), The FDA-NIMH-MATRICS guidelines for clinical trial designof cognitive-enhancing drugs: what do we know 5 years later? Schizophr.Bull. 37, 1209-1217.

In animal model systems, cognitive function may be measured in variousconventional ways known in the art, including using a Morris Water Maze(MWM), Barnes circular maze, elevated radial arm maze, T maze or anyother mazes in which the animals use spatial information. Cognitivefunction can be assessed by reversal learning, extradimensional setshifting, conditional discrimination learning and assessments of rewardexpectancy. Other tests known in the art may also be used to assesscognitive function, such as novel object recognition and odorrecognition tasks.

Cognitive function may also be measured using imaging techniques such asPositron Emission Tomography (PET), functional magnetic resonanceimaging (fMRI), Single Photon Emission Computed Tomography (SPECT), orany other imaging technique that allows one to measure brain function.In animals, cognitive function may also be measured withelectrophysiological techniques.

“Promoting” cognitive function refers to affecting impaired cognitivefunction so that it more closely resembles the function of a normal,unimpaired subject. Cognitive function may be promoted to any detectabledegree, but in humans preferably is promoted sufficiently to allow animpaired subject to carry out daily activities of normal life a level ofproficiency as close as possible to a normal, unimpaired subject or anage-matched normal, unimpaired subject.

In some cases, “promoting” cognitive function in a subject affected byage-related cognitive refers to affecting impaired cognitive function sothat it more closely resembles the function of an aged-matched normal,unimpaired subject, or the function of a young adult subject. Cognitivefunction of that subject may be promoted to any detectable degree, butin humans preferably is promoted sufficiently to allow an impairedsubject to carry out daily activities of normal life at a level ofproficiency as close as possible to a normal, unimpaired subject or ayoung adult subject or an age-matched normal, unimpaired subject.

“Preserving” cognitive function refers to affecting normal or impairedcognitive function such that it does not decline or does not fall belowthat observed in the subject upon first presentation or diagnosis, ordelays such decline.

“Improving” cognitive function includes promoting cognitive functionand/or preserving cognitive function in a subject.

“Cognitive impairment” refers to cognitive function in subjects that isnot as robust as that expected in a normal, unimpaired subject. In somecases, cognitive function is reduced by about 5%, about 10%, about 30%,or more, compared to cognitive function expected in a normal, unimpairedsubject. In some cases, “cognitive impairment” in subjects affected byaged-related cognitive impairment refers to cognitive function insubjects that is not as robust as that expected in an aged-matchednormal, unimpaired subject, or the function of a young adult subject(i.e. subjects with mean scores for a given age in a cognitive test).

“Treating” a condition or patient refers to taking steps to obtainbeneficial or desired results, including clinical results. Beneficial ordesired clinical results include, but are not limited to, improvingcognitive function, delaying or slowing the progression of cognitiveimpairment, reducing the rate of decline of cognitive function,preventing or slowing the progression of the disease or disorder, oralleviation, amelioration, or slowing the progression, of one or moresymptoms associated of cognitive impairment associated with CNSdisorders, such as age-related cognitive impairment, Mild CognitiveImpairment (MCI), amnestic MCI, dementia, Alzheimer's Disease (AD),prodromal AD, PTSD, schizophrenia or bipolar disorder (in particular,mania), amyotrophic lateral sclerosis (ALS) or cancer therapy-relatedcognitive impairment. Treating age-related cognitive impairment furthercomprises slowing the conversion of age-related cognitive impairment(including, but not limited to MCI, ARCD and AAMI) into dementia (e.g.,AD).

“Treating cognitive impairment” refers to taking steps to improvecognitive function in a subject with cognitive impairment so that thesubject's performance in one or more cognitive tests is improved to anydetectable degree, or is prevented from further decline. Preferably,that subject's cognitive function, after treatment of cognitiveimpairment, more closely resembles the function of a normal, unimpairedsubject. Treatment of cognitive impairment in humans may improvecognitive function to any detectable degree, but is preferably improvedsufficiently to allow the impaired subject to carry out daily activitiesof normal life at the same level of proficiency as a normal, unimpairedsubject. In some cases, “treating cognitive impairment” refers to takingsteps to improve cognitive function in a subject with cognitiveimpairment so that the subject's performance in one or more cognitivetests is improved to any detectable degree, or is prevented from furtherdecline. Preferably, that subject's cognitive function, after treatmentof cognitive impairment, more closely resembles the function of anormal, unimpaired subject. In some cases, “treating cognitiveimpairment” in a subject affecting by age-related cognitive impairmentrefers to takings steps to improve cognitive function in the subject sothat the subject's cognitive function, after treatment of cognitiveimpairment, more closely resembles the function of an age-matchednormal, unimpaired subject, or the function of a young adult subject. Insome cases, “treating cognitive impairment” in a subject refers totaking steps to delay or slow the progression of cognitive impairment ina subject with cognitive impairment. In some cases, “treating cognitiveimpairment” in a subject refers to taking steps to reduce the rate ofdecline of cognitive function in a subject with cognitive impairment.

The term “agent” is used herein to denote a chemical compound (such asan organic or inorganic compound, a mixture of chemical compounds), abiological macromolecule (such as a nucleic acid, an antibody, includingparts thereof as well as humanized, chimeric and human antibodies andmonoclonal antibodies, a protein or portion thereof, e.g., a peptide, alipid, a carbohydrate), or an extract made from biological materialssuch as bacteria, plants, fungi, or animal (particularly mammalian)cells or tissues. Agents include, for example, agents which are knownwith respect to structure, and those which are not known with respect tostructure.

Description of Compositions of the Invention

This invention provides extended release compositions of levetiracetam.The compositions of this invention can be used for improving cognitionin patients who suffer from cognitive impairment associated with centralnervous system (CNS) disorders in a subject in need or at risk thereof.The compositions of this invention is administered once a day (i.e.,once every 24 hours) for improving cognition.

In one aspect, the invention provides extended release pharmaceuticalcompositions comprising: a) 220 mg of levetiracetam; b) 280 mg to 350 mgof hydroxypropyl methylcellulose (or hypromellose); c) 1.2 mg to 1.4 mgof colloidal silicon dioxide; d) 92.8 mg-119.2 mg of silicifiedmicrocrystalline cellulose; and e) 6.0 mg to 6.7 mg of magnesiumstearate. In some embodiments, the hydroxypropyl methylcellulose (orhypromellose) is Methocel™ K15M CR. In some embodiments, thehydroxypropyl methylcellulose (or hypromellose) is Methocel™ K100MPremium CR. In some embodiments, the silicified microcrystallinecellulose is ProSolv™ HD90. In some embodiments, the magnesium stearateis HyQual®. In some embodiments, the extended release pharmaceuticalcomposition is in a solid form. In some embodiments, the extendedrelease pharmaceutical composition is in the form of a tablet orcapsule.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 220 mg of levetiracetam; b)280 mg of hydroxypropyl methylcellulose (or hypromellose); c) 1.2 mg ofcolloidal silicon dioxide; d) 92.8 mg of silicified microcrystallinecellulose; and e) 6.0 mg of magnesium stearate. In some embodiments, thehydroxypropyl methylcellulose (or hypromellose) is Methocel™ K15M CR. Insome embodiments, the hydroxypropyl methylcellulose (or hypromellose) isMethocel™ K100M Premium CR. In some embodiments, the silicifiedmicrocrystalline cellulose is ProSolv™ HD90. In some embodiments, themagnesium stearate is HyQual®. In some embodiments, the extended releasepharmaceutical composition is in a solid form. In some embodiments, theextended release pharmaceutical composition is in the form of a tabletor capsule.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 220 mg of levetiracetam; b)347.5 mg of hydroxypropyl methylcellulose (or hypromellose); c) 1.4 mgof colloidal silicon dioxide; d) 119.2 mg of silicified microcrystallinecellulose; and e) 6.7 mg of magnesium stearate. In some embodiments, thehydroxypropyl methylcellulose (or hypromellose) is Methocel™ K15M CR. Insome embodiments, the hydroxypropyl methylcellulose (or hypromellose) isMethocel™ K100M Premium CR. In some embodiments, the silicifiedmicrocrystalline cellulose is ProSolv™ HD90. In some embodiments, themagnesium stearate is HyQual®. In some embodiments, the extended releasepharmaceutical composition is in a solid form. In some embodiments, theextended release pharmaceutical composition is in the form of a tabletor capsule.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 220 mg of levetiracetam; b)280 mg of hydroxypropyl methylcellulose (or hypromellose) Methocel™ K15MCR; c) 1.2 mg of colloidal silicon dioxide; d) 92.8 mg of silicifiedmicrocrystalline cellulose ProSolv™ HD90; and e) 6.0 mg of magnesiumstearate (e.g., HyQual®). In some embodiments, the extended releasepharmaceutical composition is in a solid form. In some embodiments, theextended release pharmaceutical composition is in the form of a tabletor capsule.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 220 mg of levetiracetam; b)347.5 mg of hydroxypropyl methylcellulose (or hypromellose) Methocel™K15M CR; c) 1.4 mg of colloidal silicon dioxide; d) 119.2 mg ofsilicified microcrystalline cellulose ProSolv™ HD90; and e) 6.7 mg ofmagnesium stearate (e.g., HyQual®). In some embodiments, the extendedrelease pharmaceutical composition is in a solid form. In someembodiments, the extended release pharmaceutical composition is in theform of a tablet or capsule.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 190 mg of levetiracetam; b)300 mg of hydroxypropyl methylcellulose (or hypromellose); c) 1.2 mg ofcolloidal silicon dioxide; d) 102.8 mg of silicified microcrystallinecellulose; and e) 6 mg of magnesium stearate. In some embodiments, thehydroxypropyl methylcellulose (or hypromellose) is Methocel™ K15M CR. Insome embodiments, the hydroxypropyl methylcellulose (or hypromellose) isMethocel™ K100M Premium CR. In some embodiments, the silicifiedmicrocrystalline cellulose is ProSolv™ HD90. In some embodiments, themagnesium stearate is HyQual®. In some embodiments, the extended releasepharmaceutical composition is in a solid form. In some embodiments, theextended release pharmaceutical composition is in the form of a tabletor capsule.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 190 mg of levetiracetam; b)300 mg of hydroxypropyl methylcellulose (or hypromellose); c) 1.2 mg ofcolloidal silicon dioxide; d) 102.8 mg of anhydrous dicalcium phosphate;and e) 6 mg of magnesium stearate. In some embodiments, thehydroxypropyl methylcellulose (or hypromellose) is Methocel™ K15M CR. Insome embodiments, the hydroxypropyl methylcellulose (or hypromellose) isMethocel™ K100M Premium CR. In some embodiments, the magnesium stearateis HyQual®. In some embodiments, the extended release pharmaceuticalcomposition is in a solid form. In some embodiments, the extendedrelease pharmaceutical composition is in the form of a tablet orcapsule.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 190 mg of levetiracetam; b)300 mg of hydroxypropyl methylcellulose (or hypromellose) Methocel™ K15MCR; c) 1.2 mg of colloidal silicon dioxide; d) 102.8 mg of silicifiedmicrocrystalline cellulose ProSolv™ HD90; and e) 6 mg of magnesiumstearate (e.g., HyQual®). In some embodiments, the extended releasepharmaceutical composition is in a solid form. In some embodiments, theextended release pharmaceutical composition is in the form of a tabletor capsule.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 190 mg of levetiracetam; b)300 mg of hydroxypropyl methylcellulose (or hypromellose) Methocel™K100M Premium CR; c) 1.2 mg of colloidal silicon dioxide; d) 102.8 mg ofsilicified microcrystalline cellulose ProSolv™ HD90; and e) 6 mg ofmagnesium stearate (e.g., HyQual®). In some embodiments, the extendedrelease pharmaceutical composition is in a solid form. In someembodiments, the extended release pharmaceutical composition is in theform of a tablet or capsule.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 190 mg of levetiracetam; b)300 mg of hydroxypropyl methylcellulose (or hypromellose) Methocel™K100M Premium CR; c) 1.2 mg of colloidal silicon dioxide; d) 102.8 mg ofanhydrous dicalcium phosphate; and e) 6 mg of magnesium stearate (e.g.,HyQual®). In some embodiments, the extended release pharmaceuticalcomposition is in a solid form. In some embodiments, the extendedrelease pharmaceutical composition is in the form of a tablet orcapsule.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising 100-350 mg of levetiracetam, amatrix-forming polymer, a glidant, a diluent, and a lubricant. In someembodiments, the matrix-forming polymer is water soluble. In someembodiments, the diluent is water soluble. In some embodiments, theamount of levetiracetam in the extended release pharmaceuticalcompositions is 125-250 mg of levetiracetam. In some embodiments, thepercentage of the matrix-forming polymer in the extended releasepharmaceutical compositions is any range between 45% w/w-70% w/w, suchas 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65%, or 70% w/w.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 30-40% w/w (e.g., 31.7-36.7%w/w) of levetiracetam; b) 45-55% w/w (e.g., 46.7-50% w/w) ofhydroxypropyl methylcellulose (or hypromellose); c) 0.01-5% w/w ofcolloidal silicon dioxide (e.g., 0.2% w/w); d) 15-20% w/w (15.5-17.1%w/w) of silicified microcrystalline cellulose; and e) 0.01-5% w/w ofmagnesium stearate (e.g., 0.96-1% w/w). In some embodiments, thehydroxypropyl methylcellulose (or hypromellose) is Methocel™ K15M CR. Insome embodiments, the hydroxypropyl methylcellulose (or hypromellose) isMethocel™ K100M Premium CR. In some embodiments, the silicifiedmicrocrystalline cellulose is ProSolv™ HD90. In some embodiments, themagnesium stearate is HyQual®. In some embodiments, the extended releasepharmaceutical composition is in a solid form. In some embodiments, theextended release pharmaceutical composition is in the form of a tabletor capsule. In some embodiments, the total weight of the extendedrelease pharmaceutical composition is 250 mg-1000 mg. In a particularembodiment, the total weight of the extended release pharmaceuticalcomposition is 600 mg. In some embodiments, the extended releasecomposition comprises 125-250 mg of levetiracetam.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 36.7% w/w of levetiracetam;b) 46.7% w/w of hydroxypropyl methylcellulose (or hypromellose); c) 0.2%w/w of colloidal silicon dioxide; d) 15.5% w/w of silicifiedmicrocrystalline cellulose; and e) 1% w/w of magnesium stearate. In someembodiments, the hydroxypropyl methylcellulose (or hypromellose) isMethocel™ K15M CR. In some embodiments, the hydroxypropylmethylcellulose (or hypromellose) is Methocel™ K100M Premium CR. In someembodiments, the silicified microcrystalline cellulose is ProSolv™ HD90.In some embodiments, the magnesium stearate is HyQual®. In someembodiments, the extended release pharmaceutical composition is in asolid form. In some embodiments, the extended release pharmaceuticalcomposition is in the form of a tablet or capsule. In some embodiments,the total weight of the extended release pharmaceutical composition is250 mg-1000 mg. In a particular embodiment, the total weight of theextended release pharmaceutical composition is 600 mg. In someembodiments, the extended release composition comprises 125-250 mg oflevetiracetam.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam;b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose); c) 0.2%w/w mg of colloidal silicon dioxide; d) 17.1% w/w of silicifiedmicrocrystalline cellulose; and e) 0.96% w/w of magnesium stearate. Insome embodiments, the hydroxypropyl methylcellulose (or hypromellose) isMethocel™ K15M CR. In some embodiments, the hydroxypropylmethylcellulose (or hypromellose) is Methocel™ K100M Premium CR. In someembodiments, the silicified microcrystalline cellulose is ProSolv™ HD90.In some embodiments, the magnesium stearate is HyQual®. In someembodiments, the extended release pharmaceutical composition is in asolid form. In some embodiments, the extended release pharmaceuticalcomposition is in the form of a tablet or capsule. In some embodiments,the total weight of the extended release pharmaceutical composition is250 mg-1000 mg. In a particular embodiment, the total weight of theextended release pharmaceutical composition is 695 mg. In someembodiments, the extended release composition comprises 125-250 mg oflevetiracetam.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 36.7% w/w of levetiracetam;b) 46.7% w/w of hydroxypropyl methylcellulose (or hypromellose)Methocel™ K15M CR; c) 0.2% w/w of colloidal silicon dioxide; d) 15.5%w/w of silicified microcrystalline cellulose ProSolv™ HD90; and e) 1%w/w of magnesium stearate (e.g., HyQual®). In some embodiments, theextended release pharmaceutical composition is in a solid form. In someembodiments, the extended release pharmaceutical composition is in theform of a tablet or capsule. In some embodiments, the total weight ofthe extended release pharmaceutical composition is 250 mg-1000 mg. In aparticular embodiment, the total weight of the extended releasepharmaceutical composition is 600 mg. In some embodiments, the extendedrelease composition comprises 125-250 mg of levetiracetam.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 31.7 % w/w of levetiracetam;b) 50% w/w of dhydroxypropyl methylcellulose (or hypromellose) Methocel™K15M CR; c) 0.2% w/w of colloidal silicon dioxide; d) 17.1% w/w ofsilicified microcrystalline cellulose ProSolv™ HD90; and e) 0.96% w/w ofmagnesium stearate (e.g., HyQual®). In some embodiments, the extendedrelease pharmaceutical composition is in a solid form. In someembodiments, the extended release pharmaceutical composition is in theform of a tablet or capsule. In some embodiments, the total weight ofthe extended release pharmaceutical composition is 250 mg-1000 mg. In aparticular embodiment, the total weight of the extended releasepharmaceutical composition is 695 mg. In some embodiments, the extendedrelease composition comprises 125-250 mg of levetiracetam.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam;b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose); c) 0.2%w/w of colloidal silicon dioxide; d) 17.1% w/w of silicifiedmicrocrystalline cellulose; and e) 1% w/w of magnesium stearate. In someembodiments, the hydroxypropyl methylcellulose (or hypromellose) isMethocel™ K15M CR. In some embodiments, the hydroxypropylmethylcellulose (or hypromellose) is Methocel™ K100M Premium CR. In someembodiments, the silicified microcrystalline cellulose is ProSolv™ HD90.In some embodiments, the magnesium stearate is HyQual®. In someembodiments, the extended release pharmaceutical composition is in asolid form. In some embodiments, the extended release pharmaceuticalcomposition is in the form of a tablet or capsule. In some embodiments,the total weight of the extended release pharmaceutical composition is250 mg-1000 mg. In a particular embodiment, the total weight of theextended release pharmaceutical composition is 600 mg. In someembodiments, the extended release composition comprises 125-250 mg oflevetiracetam.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam;b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose); c) 0.2%w/w of colloidal silicon dioxide; d) 17.1% w/w of anhydrous dicalciumphosphate; and e) 1% w/w of magnesium stearate. In some embodiments, thehydroxypropyl methylcellulose (or hypromellose) is Methocel™ K15M CR. Insome embodiments, the hydroxypropyl methylcellulose (or hypromellose) isMethocel™ K100M Premium CR. In some embodiments, the magnesium stearateis HyQual®. In some embodiments, the extended release pharmaceuticalcomposition is in a solid form. In some embodiments, the extendedrelease pharmaceutical composition is in the form of a tablet orcapsule. In some embodiments, the total weight of the extended releasepharmaceutical composition is 250 mg-1000 mg. In a particularembodiment, the total weight of the extended release pharmaceuticalcomposition is 600 mg. In some embodiments, the extended releasecomposition comprises 125-250 mg of levetiracetam.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam;b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose) Methocel™K15M CR; c) 0.2% w/w of colloidal silicon dioxide; d) 17.1% w/w ofsilicified microcrystalline cellulose ProSolv™ HD90; and e) 1% w/w ofmagnesium stearate (e.g., HyQual®). In some embodiments, the extendedrelease pharmaceutical composition is in a solid form. In someembodiments, the extended release pharmaceutical composition is in theform of a tablet or capsule. In some embodiments, the total weight ofthe extended release pharmaceutical composition is 250 mg-1000 mg. In aparticular embodiment, the total weight of the extended releasepharmaceutical composition is 600 mg. In some embodiments, the extendedrelease composition comprises 125-250 mg of levetiracetam.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam;b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose) Methocel™K100M Premium CR; c) 0.2% w/w of colloidal silicon dioxide; d) 17.1% w/wof silicified microcrystalline cellulose ProSolv™ HD90; and e) 1% w/w ofmagnesium stearate (e.g., HyQual®). In some embodiments, the extendedrelease pharmaceutical composition is in a solid form. In someembodiments, the extended release pharmaceutical composition is in theform of a tablet or capsule. In some embodiments, the total weight ofthe extended release pharmaceutical composition is 250 mg-1000 mg. In aparticular embodiment, the total weight of the extended releasepharmaceutical composition is 600 mg. In some embodiments, the extendedrelease composition comprises 125-250 mg of levetiracetam.

In another aspect, the invention provides extended releasepharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam;b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose) Methocel™K100M Premium CR; c) 0.2% w/w of colloidal silicon dioxide; d) 17.1% w/wof anhydrous dicalcium phosphate; and e) 1% w/w of magnesium stearateHyQual®. In some embodiments, the extended release pharmaceuticalcomposition is in a solid form. In some embodiments, the extendedrelease pharmaceutical composition is in the form of a tablet orcapsule. In some embodiments, the total weight of the extended releasepharmaceutical composition is 250 mg-1000 mg. In a particularembodiment, the total weight of the extended release pharmaceuticalcomposition is 600 mg. In some embodiments, the extended releasecomposition comprises 125-250 mg of levetiracetam.

In some embodiments, the invention uses hydroxypropyl methylcellulose(or hypromellose) as a rate controlling polymer or a matrix formingpolymer in the extended release compositions. In some embodiments,hydroxypropyl methylcellulose (or hypromellose) can be used togetherwith other rate controlling polymers or matrix forming polymers in thecompositions of this invention. In some embodiments, hydroxypropylmethylcellulose can be replaced by other rate controlling polymers ormatrix forming polymers in the compositions of this invention. In someembodiments, the rate controlling polymers or matrix forming polymersthat can replace hydroxypropyl methylcellulose or be used together withhydroxypropyl methylcellulose have similar properties or characteristicsas hydroxypropyl methylcellulose. Examples of these rate controllingpolymers or matrix forming polymers include, without being limited to,cellulose, non-cellulose polysaccharide, polyvinyl polymer, hydrogel,monolithic polymer, or mixtures thereof. In some embodiments,hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, methylcellulose, sodium carboxymethyl cellulose, sodiumalginate, carbomer, xanthan gum, guar gum, locust bean gum, carob gum,arabic gum, sterculia gum, polyvinyl pyrrolidone, polyvinyl acetate,polyvinyl alcohol, polyethylene oxide, or a mixture thereof can be usedas a rate controlling polymer or matrix forming polymer in thecompositions of the invention. In some embodiments, the hydroxypropylmethylcellulose (or hypromellose) in the compositions of the presentinvention may be selected from the group consisting of Methocel™ K4M,K15M, K100M, E4M, E10M, K4M CR, K15M CR, K100M CR, E4M CR, E10M CR, K4MPremium, K15M Premium, K100M Premium, E4M Premium, E10M Premium, K4MPremium CR, K15M Premium CR, K100M Premium CR, E4M Premium CR, E10MPremium CR, and K100 Premium LV.

In some embodiments, the invention uses colloidal silicon dioxide as aglidant in the extended release compositions. In some embodiments,colloidal silicon dioxide can be used together with other glidants inthe compositions of this invention. In some embodiments, colloidalsilicon dioxide can be replaced by other glidants in the compositions ofthis invention. In some embodiments, the glidant that can replacecolloidal silicon dioxide or that can be used together with colloidalsilicon dioxide have similar properties or characteristics as colloidalsilicon dioxide. Examples of these glidants include, without beinglimited to, cornstarch, talc, calcium silicate, magnesium silicate,aluminum silicate, silicon hydrogel or a mixture thereof.

In some embodiments, the invention uses silicified microcrystallinecellulose as a diluent in the extended release compositions. In someembodiments, silicified microcrystalline cellulose can be used togetherwith other diluents in the compositions of this invention. In someembodiments, silicified microcrystalline cellulose can be replaced byother diluents in the compositions of this invention. In someembodiments, the diluent that can replace silicified microcrystallinecellulose or that can be used together with silicified microcrystallinecellulose have similar properties or characteristics as silicifiedmicrocrystalline cellulose, such as water solubility. Examples of thesediluents (or water soluble diluents) include, without being limited to,microcrystalline cellulose, lactose, mannitol, xylitol, dextrose,sucrose, sorbitol, compressible sugar, powdered cellulose, cornstarch,pregelatinized starch, dextrate, dextran, dextrin, dextrose,maltodextrin, calcium carbonate, polyethylene oxide, and a mixturethereof.

In some embodiments, the invention uses magnesium stearate as alubricant in the extended release compositions. In some embodiments,magnesium stearate can be used together with other lubricants in thecompositions of this invention. In some embodiments, magnesium stearatecan be replaced by other lubricants in the compositions of thisinvention. In some embodiments, the lubricant that can replace magnesiumstearate or that can be used together with magnesium stearate havesimilar properties or characteristics as magnesium stearate. Examples ofthese lubricants include, without being limited to, calcium stearate,sodium stearyl fumerate, glyceryl palmitostearate, glyceryl stearate,mineral oil, stearic acid, zinc stearate and a mixture thereof

The compositions described herein can further contain pharmaceuticallyacceptable excipient(s) and may contain other agents that serve toenhance and/or complement the effectiveness of the levetiracetam, or toenhance or improve the extended release profile or pharmacokineticprofile of the levetiracetam.

In some embodiments, the pharmaceutical composition of the presentinvention is the formulations in Table 1. In one embodiment, thepharmaceutical composition of the present invention is the 190 mg TabletA formulation.

In some embodiments, the pharmaceutical composition of the presentinvention is the formulations in Table 3. In one embodiment, thepharmaceutical composition of the present invention is the 220 mg TabletD formulation.

In some embodiments, the extended release levetiracetam compositions areformulated for once daily administration. For example, the extendedrelease compositions comprise 190 mg of levetiracetam and provide adaily dosage of 190 mg when administered once a day (i.e., everytwenty-four hours). The extended release compositions comprise 220 mg oflevetiracetam and provide a daily dosage of 220 mg when administeredonce a day (i.e., every twenty-four hours). In some embodiments, theextended release levetiracetam compositions are formulated forone-unit-dosage-form-once-daily administration. In some embodiments, theextended release levetiracetam compositions are formulated forone-tablet-once-daily administration. For example, subjects who sufferfrom cognitive impairment will take the extended release composition ofthe invention (e.g., Tablets A, B, and C in Table 1 or Tablets D and Ein Table 3) one-tablet-once-a-day. Each tablet is an extended releasedosage form comprising 190 mg or 220 mg of levetiracetam.

In some embodiments, the extended release levetiracetam compositions areadministered in the morning.

In some embodiments, the extended release levetiracetam compositions arein a solid form, for example, tablets, capsules, mini-tablets, minitablets in a capsule, dragrees, pills, lozenges, granules, films ordissolvable films. In some embodiments, the compositions of the presentinvention are in the form of a tablet. In some embodiments, the tabletis a homogeneous mixture.

In some embodiments, the extended release levetiracetam compositions areformulated for oral administration. In some embodiments, the extendedrelease pharmaceutical compositions are formulated in a solid form fororal administration. In some embodiments, the extended releaselevetiracetam compositions are oral tablets. In some embodiments, theextended release levetiracetam compositions are oral capsules. In someembodiments, the extended release levetiracetam compositions areformulated for injection or sublingual administration. In someembodiments, the extended release levetiracetam compositions areformulated for administration in the form of a patch or a pump.

In some embodiments, the pharmaceutical compositions of the invention donot comprise a hydrophobic rate controlling polymer.

In some embodiments, the pharmaceutical compositions of the invention donot comprise a functional coating.

Description of Methods of the Invention

The methods of this invention comprise administration of the extendedrelease compositions of levetiracetam for treating cognitive impairmentassociated with central nervous system (CNS) disorders in a subject inneed or at risk thereof, including, without limitation, subjects havingor at risk for age-related cognitive impairment, Mild CognitiveImpairment (MCI), amnestic MCI (aMCI), Age-Associated Memory Impairment(AAMI), Age Related Cognitive Decline (ARCD), dementia, Alzheimer'sDisease(AD), prodromal AD, post traumatic stress disorder (PTSD),schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS),cancer-therapy-related cognitive impairment, mental retardation,Parkinson's disease (PD), autism, compulsive behavior, and substanceaddiction.

In some embodiments, treatment comprises improving cognitive function inpatients suffering from or at risk for cognitive impairment associatedwith a CNS disorder, such as age-related cognitive impairment, MildCognitive Impairment (MCI), amnestic MCI (aMCI), Age-Associated MemoryImpairment (AAMI), Age Related Cognitive Decline (ARCD), dementia,Alzheimer's Disease(AD), prodromal AD, post traumatic stress disorder(PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis(ALS), cancer-therapy-related cognitive impairment, mental retardation,Parkinson's disease (PD), autism, compulsive behavior, and substanceaddiction. In certain embodiments, treatment comprises slowing ordelaying the progression of the CNS disorder. In certain embodiments,treatment comprises preventing, slowing, or delaying the progression ofcognitive impairment associated with the CNS disorder. In certainembodiments, treatment comprises reducing the rate of decline ofcognitive function associated with the CNS disorder. In certainembodiments, treatment comprises alleviation, amelioration or slowingthe progression, of one or more symptoms associated with the CNSdisorder, such as cognitive impairment.

Methods of Assessing Cognitive Impairment

Animal models serve as an important resource for developing andevaluating treatments for cognitive impairment associated with CNSdisorders. Features that characterize cognitive impairment in animalmodels typically extend to cognitive impairment in humans. Efficacy insuch animal models is, thus, expected to be predictive of efficacy inhumans. The extent of cognitive impairment in an animal model for a CNSdisorder, and the efficacy of a method of treatment for said CNSdisorder may be tested and confirmed with the use of a variety ofcognitive tests.

A Radial Arm Maze (RAM) behavioral task is one example of a cognitivetest, specifically testing spacial memory (Chappell et al.Neuropharmacology 37: 481-487, 1998). The RAM apparatus consists of,e.g., eight equidistantly spaced arms. A maze arm projects from eachfacet of a center platform. A food well is located at the distal end ofeach arm. Food is used as a reward. Blocks can be positioned to prevententry to any arm. Numerous extra maze cues surrounding the apparatus mayalso be provided. After habituation and training phases, spatial memoryof the subjects may be tested in the RAM under control or testcompound-treated conditions. As a part of the test, subjects arepretreated before trials with a vehicle control or one of a range ofdosages of the test compound. At the beginning of each trial, a subsetof the arms of the eight-arm maze is blocked. Subjects are allowed toobtain food on the unblocked arms to which access is permitted duringthis initial “information phase” of the trial. Subjects are then removedfrom the maze for a delay period, e.g., a 60 second delay, a 15 minutedelay, a one-hour delay, a two-hour delay, a six hour delay, a 24 hourdelay, or longer) between the information phase and the subsequent“retention test,” during which the barriers on the maze are removed,thus allowing access to all eight arms. After the delay period, subjectsare placed back onto the center platform (with the barriers to thepreviously blocked arms removed) and allowed to obtain the remainingfood rewards during this retention test phase of the trial. The identityand configuration of the blocked arms vary across trials. The number of“errors” the subjects make during the retention test phase is tracked.An error occurs in the trial if the subjects entered an arm from whichfood had already been retrieved in the pre-delay component of the trial,or if it re-visits an arm in the post-delay session that had alreadybeen visited. A fewer number of errors would indicate better spatialmemory. The number of errors made by the test subject, under varioustest compound treatment regimes, can then be compared for efficacy ofthe test compound in treating cognitive impairment associated with CNSdisorders.

Another cognitive test that may be used to assess the effects of a testcompound on the cognitive impairment of a CNS disorder model animal isthe Morris water maze. A water maze is a pool surrounded with a novelset of patterns relative to the maze. The training protocol for thewater maze may be based on a modified water maze task that has beenshown to be hippocampal-dependent (de Hoz et al., Eur. J Neurosci.,22:745-54, 2005; Steele and Morris, Hippocampus 9:118-36, 1999). Thesubject is trained to locate a submerged escape platform hiddenunderneath the surface of the pool. During the training trial, a subjectis released in the maze (pool) from random starting positions around theperimeter of the pool. The starting position varies from trial to trial.If the subject does not locate the escape platform within a set time,the experimenter guides and places the subject on the platform to“teach” the location of the platform. After a delay period following thelast training trial, a retention test in the absence of the escapeplatform is given to assess spatial memory. The subject's level ofpreference for the location of the (now absent) escape platform, asmeasured by, e.g., the time spent in that location or the number ofcrossings of that location made by the mouse, indicates better spatialmemory, i.e., treatment of cognitive impairment. The preference for thelocation of the escape platform under different treatment conditions,can then be compared for efficacy of the test compound in treatingcognitive impairment associated with CNS disorders.

There are various tests known in the art for assessing cognitivefunction in humans, for example and without limitation, the clinicalglobal impression of change scale (CIBIC-plus scale); the Mini MentalState Exam (MMSE); the Neuropsychiatric Inventory (NPI); the ClinicalDementia Rating Scale (CDR); the Cambridge Neuropsychological TestAutomated Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric(SCAG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974);the Verbal Paired Associates subtest; the Logical Memory subtest; theVisual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R)(Wechsler, 1997); the Benton Visual Retention Test, or MATRICS consensusneuropsychological test battery which includes tests of working memory,speed of processing, attention, verbal learning, visual learning,reasoning and problem solving and social cognition. See Folstein et al.,J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger etal., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002and Masur et al., 1994, or MATRICS consensus neuropsychological testbattery which includes tests of working memory, speed of processing,attention, verbal learning, visual learning, reasoning and problemsolving and social cognition. Another example of a cognitive test inhumans is the explicit 3-alternative forced choice task. In this test,subjects are presented with color photographs of common objectsconsisting of a mix of three types of image pairs: similar pairs,identical pairs and unrelated foils. The second of the pair of similarobjects is referred to as the “lure”. These image pairs are fullyrandomized and presented individually as a series of images. Subjectsare instructed to make a judgment as to whether the objects seen arenew, old or similar. A “similar” response to the presentation of a lurestimulus indicates successful memory retrieval by the subject. Bycontrast, calling the lure stimulus “old” or “new” indicates thatcorrect memory retrieval does not occur.

In addition to assessing cognitive performance, the progression ofage-related cognitive impairment and dementia, as well as the conversionof age-related cognitive impairment into dementia, may be monitored byassessing surrogate changes in the brain of the subject. Surrogatechanges include, without limitation, changes in regional brain volumes,perforant path degradation, and changes seen in brain function throughresting state fMRI (R-fMRI) and fluorodeoxyglucose positron emissiontomography (FDG-PET). Examples of regional brain volumes useful inmonitoring the progression of age-related cognitive impairment anddementia include reduction of hippocampal volume and reduction in volumeor thickness of entorhinal cortex. These volumes may be measured in asubject by, for example, MRI. Aisen et al., Alzheimer's & Dementia6:239-246 (2010). Perforant path degradation has been shown to be linkedto age, as well as reduced cognitive function. For example, older adultswith more perforant path degradation tend to perform worse inhippocampus-dependent memory tests. Perforant path degradation may bemonitored in subjects through ultrahigh-resolution diffusion tensorimaging (DTI). Yassa et al., PNAS 107:12687-12691 (2010). Resting-statefMRI (R-fMRI) involves imaging the brain during rest, and recordinglarge-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in thefMRI signal that are temporally correlated across functionally relatedareas. Seed-based functional connectivity, independent componentanalyses, and/or frequency-domain analyses of the signals are used toreveal functional connectivity between brain areas, particularly thoseareas whose connectivity increase or decrease with age, as well as theextent of cognitive impairment and/or dementia. FDG-PET uses the uptakeof FDG as a measure of regional metabolic activity in the brain. Declineof FDG uptake in regions such as the posterior cingulated cortex,temporoparietal cortex, and prefrontal association cortex has been shownto relate to the extent of cognitive decline and dementia. Aisen et al.,Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., Neurolmage17:302-316 (2002).

Age-Related Cognitive Impairment

This invention provides methods for treating age-related cognitiveimpairment or the risk thereof using the extended release levetiracetamcompositions of the invention. In certain embodiments, treatmentcomprises improving cognitive function in patients with age-relatedcognitive impairment. In certain embodiments, treatment comprisesslowing or delaying the progression of age-related cognitive impairment.In certain embodiments, treatment comprises reducing the rate of declineof cognitive function associated with age-related cognitive impairment.In certain embodiments, treatment comprises preventing or slowing theprogression, of age-related cognitive impairment. In certainembodiments, treatment comprises alleviation, amelioration or slowingthe progression, of one or more symptoms associated with age-relatedcognitive impairment. In certain embodiments, treatment of age-relatedcognitive impairment comprises slowing the conversion of age-relatedcognitive impairment (including, but not limited to MCI, ARCD and AAMI)into dementia (e.g., AD). The methods and compositions may be used forhuman patients in clinical applications in the treating age-relatedcognitive impairment in conditions such as MCI, ARCD and AAMI or for therisk thereof. The dose of the composition and dosage interval for themethod is, as described herein, one that is safe and efficacious inthose applications.

In some embodiments, a subject to be treated by the methods andcompositions of this invention exhibits age-related cognitive impairmentor is at risk of such impairment. In some embodiments, the age-relatedcognitive impairment includes, without limitation, Age-Associated MemoryImpairment (AAMI), Mild Cognitive Impairment (MCI) and Age-relatedCognitive Decline (ARCD).

Animal models serve as an important resource for developing andevaluating treatments for such age-related cognitive impairments.Features that characterize age-related cognitive impairment in animalmodels typically extend to age-related cognitive impairment in humans.Efficacy in such animal models is, thus, expected to be predictive ofefficacy in humans.

Various animal models of age-related cognitive impairment are known inthe art. For example, extensive behavioral characterization hasidentified a naturally occurring form of cognitive impairment in anoutbred strain of aged Long-Evans rats (Charles River Laboratories;Gallagher et al., Behav. Neurosci. 107:618-626, (1993)). In a behavioralassessment with the Morris Water Maze (MWM), rats learn and remember thelocation of an escape platform guided by a configuration of spatial cuessurrounding the maze. The cognitive basis of performance is tested inprobe trials using measures of the animal's spatial bias in searchingfor the location of the escape platform. Aged rats in the studypopulation have no difficulty swimming to a visible platform, but anage-dependent impairment is detected when the platform is camouflaged,requiring the use of spatial information. Performance for individualaged rats in the outbred Long-Evans strain varies greatly. For example,a proportion of those rats perform on a par with young adults. However,approximately 40-50% fall outside the range of young performance. Thisvariability among aged rats reflects reliable individual differences.Thus, within the aged population some animals are cognitively impairedand designated aged-impaired (AI) and other animals are not impaired andare designated aged-unimpaired (AU). See, e.g., Colombo et al., Proc.Natl. Acad. Sci. 94: 14195-14199, (1997); Gallagher and Burwell,Neurobiol. Aging 10: 691-708, (1989); Gallagher et al. Behav. Neurosci.107:618-626, (1993); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93:9926-9930, (1996); Nicolle et al., Neuroscience 74: 741-756, (1996);Nicolle et al., J. Neurosci. 19: 9604-9610, (1999); International PatentPublication WO2007/019312 and International Patent Publication WO2004/048551. Such an animal model of age-related cognitive impairmentmay be used to assay the effectiveness of the methods and compositionsthis invention in treating age-related cognitive impairment.

The efficacy of the methods and compositions of this invention intreating age-related cognitive impairment may be assessed using avariety of cognitive tests, including the Morris water maze and theradial arm maze, as discussed above.

Dementia

This invention also provides methods for treating dementia using theextended release levetiracetam compositions of the invention. In certainembodiments, treatment comprises improving cognitive function inpatients with dementia. In certain embodiments, treatment comprisesslowing or delaying the progression of dementia. In certain embodiments,treatment comprises reducing the rate of decline of cognitive functionassociated with dementia. In certain embodiments, treatment comprisespreventing or slowing the progression, of dementia. In certainembodiments, treatment comprises alleviation, amelioration, or slowingthe progression of one or more symptoms associated with dementia. Incertain embodiments, the symptom to be treated is cognitive impairment.In certain embodiments, the dementia is Alzheimer's disease (AD),vascular dementia, dementia with Lewy bodies, or frontotemporaldementia. The methods and compositions may be used for human patients inclinical applications in treating dementia. The dose of the compositionand dosage interval for the method is, as described herein, one that issafe and efficacious in those applications.

Animal models serve as an important resource for developing andevaluating treatments for dementia. Features that characterize dementiain animal models typically extend to dementia in humans. Thus, efficacyin such animal models is expected to be predictive of efficacy inhumans. Various animal models of dementia are known in the art, such asthe PDAPP, Tg2576, APP23, TgCRND8, J20, hPS2 Tg, and APP+PSI transgenicmice. Sankaranarayanan, Curr. Top. Medicinal Chem. 6: 609-627, 2006;Kobayashi et al. Genes Brain Behav. 4: 173-196. 2005; Ashe and Zahns,Neuron. 66: 631-45, 2010. Such animal models of dementia may be used toassay the effectiveness of the methods and compositions of thisinvention of the invention in treating dementia.

The efficacy of the methods and compositions of this invention intreating dementia, or cognitive impairment associated with dementia, maybe assessed in animals models of dementia, as well as human subjectswith dementia, using a variety of cognitive tests known in the art, asdiscussed above.

Post Traumatic Stress Disorder

This invention also provides methods for treating post traumatic stressdisorder (PTSD) using the extended release levetiracetam compositions ofthe invention. In certain embodiments, treatment comprises improvingcognitive function in patients with PTSD. In certain embodiments,treatment comprises slowing or delaying the progression of PTSD. Incertain embodiments, treatment comprises reducing the rate of decline ofcognitive function associated with PTSD. In certain embodiments,treatment comprises preventing or slowing the progression, of PTSD. Incertain embodiments, treatment comprises alleviation, amelioration, orslowing the progression of one or more symptoms associated with PTSD. Incertain embodiments, the symptom to be treated is cognitive impairment.The methods and compositions may be used for human patients in clinicalapplications in treating PTSD. The dose of the composition and dosageinterval for the method is, as described herein, one that is safe andefficacious in those applications.

Patients with PTSD (and, to a lesser degree trauma-exposed patientswithout PTSD) have smaller hippocampal volumes (Woon et al., Prog.Neuro-Psychopharm. & Biological Psych. 34, 1181-1188; Wang et al., Arch.Gen. Psychiatry 67:296-303, 2010). PTSD is also associated with impairedcognitive performance. Older individuals with PTSD have greater declinesin cognitive performance relative to control patients (Yehuda et al.,Bio. Psych. 60: 714-721, 2006) and have a greater likelihood ofdeveloping dementia (Yaffe et al., Arch. Gen. Psych. 678: 608-613,2010).

Animal models serve as an important resource for developing andevaluating treatments for PTSD. Features that characterize PTSD inanimal models typically extend to PTSD in humans. Thus, efficacy in suchanimal models is expected to be predictive of efficacy in humans.Various animal models of PTSD are known in the art.

One rat model of PTSD is Time-dependent sensitization (TDS). TDSinvolves exposure of the animal to a severely stressful event followedby a situational reminder of the prior stress. The following is anexample of TDS. Rats are placed in a restrainer, then placed in a swimtank and made to swim for a period of time, e.g., 20 min. Followingthis, each rat is then immediately exposed to a gaseous anesthetic untilloss of consciousness, and finally dried. The animals are leftundisturbed for a number of days, e.g., one week. The rats are thenexposed to a “restress” session consisting of an initial stressor, e.g.,a swimming session in the swim tank (Liberzon et al.,Psychoneuroendocrinology 22: 443-453, 1997; Harvery et al.,Psychopharmacology 175:494-502, 2004). TDS results in an enhancement ofthe acoustic startle response (ASR) in the rat, which is comparable tothe exaggerated acoustic startle that is a prominent symptom of PTSD(Khan and Liberzon, Psychopharmacology 172: 225-229, 2004). Such animalmodels of PTSD may be used to assay the effectiveness of the methods andcompositions of this invention of the invention in treating PTSD.

The efficacy of the methods and compositions of this invention intreating PTSD, or cognitive impairment associated with PTSD, may also beassessed in animals models of PTSD, as well as human subjects with PTSD,using a variety of cognitive tests known in the art, as discussed above.

Schizophrenia

This invention provides methods for treating schizophrenia or bipolardisorder (in particular, mania) using the extended release levetiracetamcompositions of the invention. In certain embodiments, treatmentcomprises improving cognitive function in patients with schizophrenia.In certain embodiments, treatment comprises slowing or delaying theprogression of schizophrenia. In certain embodiments, treatmentcomprises reducing the rate of decline of cognitive function associatedwith schizophrenia. In certain embodiments, treatment comprisespreventing or slowing the progression of schizophrenia or bipolardisorder (in particular, mania). Schizophrenia is characterized by awide spectrum of psychopathology, including positive symptoms such asaberrant or distorted mental representations (e.g., hallucinations,delusions), negative symptoms characterized by diminution of motivationand adaptive goal-directed action (e.g., anhedonia, affectiveflattening, avolition), and cognitive impairment. In certainembodiments, treatment comprises alleviation, amelioration or slowingthe progression of one or more positive and/or negative symptoms, aswell as cognitive impairment, associated with schizophrenia. Further,there are a number of other psychiatric diseases such as schizotypicaland schizoaffective disorder, other acute- and chronic psychoses andbipolar disorder (in particular, mania), which have an overlappingsymptomatology with schizophrenia. In some embodiments, treatmentcomprises alleviation, amelioration or slowing the progression of one ormore symptoms, as well as cognitive impairment, associated with bipolardisorder (in particular, mania). The methods and compositions may beused for human patients in clinical applications in treatingschizophrenia or bipolar disorder (in particular, mania). The dose ofthe composition and dosage interval for the method is, as describedherein, one that is safe and efficacious in those applications.

Cognitive impairments are associated with schizophrenia. They precedethe onset of psychosis and are present in non-affected relatives. Thecognitive impairments associated with schizophrenia constitute a goodpredictor for functional outcome and are a core feature of the disorder.Cognitive features in schizophrenia reflect dysfunction in frontalcortical and hippocampal circuits. Patients with schizophrenia alsopresent hippocampal pathologies such as reductions in hippocampalvolume, reductions in neuronal size and dysfunctional hyperactivity. Animbalance in excitation and inhibition in these brain regions has alsobeen documented in schizophrenic patients suggesting that drugstargeting inhibitory mechanisms could be therapeutic. See, e.g.,Guidotti et al., Psychopharmacology 180: 191-205, 2005; Zierhut, Psych.Res. Neuroimag. 183:187-194, 2010; Wood et al., Neurolmage 52:62-63,2010; Vinkers et al., Expert Opin. Investig. Drugs 19:1217-1233, 2009;Young et al., Pharmacol. Ther. 122:150-202, 2009.

Animal models serve as an important resource for developing andevaluating treatments for schizophrenia. Features that characterizeschizophrenia in animal models typically extend to schizophrenia inhumans. Thus, efficacy in such animal models is expected to bepredictive of efficacy in humans. Various animal models of schizophreniaare known in the art.

One animal model of schizophrenia is protracted treatment withmethionine. Methionine-treated mice exhibit deficient expression ofGAD67 in frontal cortex and hippocampus, similar to those reported inthe brain of postmortem schizophrenia patients. They also exhibitprepulse inhibition of startle and social interaction deficits(Tremonlizzo et al., PNAS, 99: 17095-17100, 2002). Another animal modelof schizophrenia is methylaoxymethanol acetate (MAM)-treatment in rats.Pregnant female rats are administered MAM (20 mg/kg, intraperitoneal) ongestational day 17. MAM-treatment recapitulate a pathodevelopmentalprocess to schizophrenia-like phenotypes in the offspring, includinganatomical changes, behavioral deficits and altered neuronal informationprocessing. More specifically, MAM-treated rats display a decreaseddensity of parvalbumin-positive GABAergic interneurons in portions ofthe prefrontal cortex and hippocampus. In behavioral tests, MAM-treatedrats display reduced latent inhibition. Latent inhibition is abehavioral phenomenon where there is reduced learning about a stimulusto which there has been prior exposure with any consequence. Thistendency to disregard previously benign stimuli, and reduce theformation of association with such stimuli is believed to preventsensory overload. Low latent inhibition is indicative of psychosis.Latent inhibition may be tested in rats in the following manner. Ratsare divided into two groups. One group is pre-exposed to a tone overmultiple trials. The other group has no tone presentation. Both groupsare then exposed to an auditory fear conditioning procedure, in whichthe same tone is presented concurrently with a noxious stimulus, e.g. anelectric shock to the foot. Subsequently, both groups are presented withthe tone, and the rats' change in locomotor activity during tonepresentation is monitored. After the fear conditioning the rats respondto the tone presentation by strongly reducing locomotor activity.However, the group that has been exposed to the tone before theconditioning period displays robust latent inhibition: the suppressionof locomotor activity in response to tone presentation is reduced.MAM-treated rats, by contrast show impaired latent inhibition. That is,exposure to the tone previous to the fear conditioning procedure has nosignificant effect in suppressing the fear conditioning. (see Lodge etal., J. Neurosci., 29:2344-2354, 2009). Such animal models ofschizophrenia may be used to assay the effectiveness of the methods andcompositions of the invention in treating schizophrenia or bipolardisorder (in particular, mania).

MAM-treated rats display a significantly enhanced locomotor response (oraberrant locomotor activity) to low dose D-amphetamine administration.The MAM-treated rats also display a significantly greater number ofspontaneously firing ventral tegmental dopamine (DA) neurons. Theseresults are believed to be a consequence of excessive hippocampalactivity because in MAM-treated rats, the ventral hippocampus (vHipp)inactivation (e.g., by intra-vHipp administration of a sodium channelblocker, tetrodotoxin (TTX), to MAM rats) completely reversed theelevated DA neuron population activity and also normalized the augmentedamphetamine-induced locomotor behavior. The correlation of hippocampaldysfunction and the hyper-responsivity of the DA system is believed tounderlie the augmented response to amphetamine in MAM-treated animalsand psychosis in schizophrenia patients. See Lodge D. J. et al.Neurobiology of Disease (2007), 27(42), 11424-11430. The use ofMAM-treated rats in the above study may be suitable for use to assay theeffectiveness of the methods and compositions of the present inventionin treating schizophrenia or bipolar disorder (in particular, mania).For example, the methods and compositions of this invention maybeevaluated, using MAM-treated animals, for their effects on the centralhippocampus (vHipp) regulation, on the elevated DA neuron populationactivity and on the hyperactive locomotor response to amphetamine in theMAM-treated animals.

In MAM-treated rats, hippocampal (HPC) dysfunction leads to dopaminesystem hyperactivity. A benzodiazepine-positive allosteric modulator(PAM), selective for the α5 subunit of the GABA_(A) receptor,SH-053-2′F-R-CH₃, is tested for its effects on the output of thehippocampal (HPC). The effect of SH-053-2′F-R-CH₃ on the hyperactivelocomotor response to amphetamine in MAM-treated animals is alsoexamined. The α5GABAAR PAM reduces the number of spontaneously active DAneurons in the ventral tegmental area (VTA) of MAM rats to levelsobserved in saline-treated rats (control group), both when administeredsystemically and when directly infused into the ventral HPC. Moreover,HPC neurons in both saline-treated and MAM-treated animals showdiminished cortical-evoked responses following the α5GABAAR PAMtreatment. In addition, the increased locomotor response to amphetamineobserved in MAM-treated rats is reduced following the α5GABA_(A)R PAMtreatment. See Gill K. M et al. Neuropsychopharmacology (2011), 1-9. Theuse of MAM-treated rats in the above study may be suitable for use inthe present invention to assay the effectiveness of the methods andcompositions of the invention in treating schizophrenia or bipolardisorder (in particular, mania). For example, the methods andcompositions of this invention maybe evaluated, using MAM-treatedanimals, for their effects on the output of the hippocampal (HPC) and onthe hyperactive locomotor response to amphetamine in the MAM-treatedanimals.

Administration of MAM to pregnant rats on embryonic day 15 (E15)severely impairs spatial memory or the ability to learn the spatiallocation of four items on an eight-arm radial maze in the offspring. Inaddition, embryonic day 17 (E17) MAM-treated rats are able to reach thelevel of performance of control rats at the initial stages of training,but are unable to process and retrieve spatial information when a 30-mindelay is interposed, indicating a significant impairment in workingmemory. See Gourevitch R. et al. (2004). Behay. Pharmacol, 15, 287-292.Such animal models of schizophrenia may be used to assay theeffectiveness of the methods and compositions of the invention intreating schizophrenia or bipolar disorder (in particular, mania).

Apomorphine-induced climbing (AIC) and stereotype (AIS) in mice isanother animal model useful in this invention. Agents are administeredto mice at a desired dose level (e.g., via intraperitonealadministration). Subsequently, e.g., thirty minutes later, experimentalmice are challenges with apomorphine (e.g., with 1 mg/kg sc). Fiveminutes after the apomorphine injection, the sniffing-licking-gnawingsyndrome (stereotyped behavior) and climbing behavior induced byapomorphine are scored and recorded for each animal. Readings can berepeated every 5 min during a 30-min test session. Scores for eachanimal are totaled over the 30-min test session for each syndrome(stereotyped behavior and climbing). If an effect reached at least of50% inhibition, and ID₅₀ value (95% confidence interval) is calculatedusing a nonlinear least squares calculation with inverse prediction.Mean climbing and stereotype scores can be expressed as a percent ofcontrol values observed in vehible treated (e.g., saline-treated) micethat receive apomorphine. See Grauer S. M. et al. Psychopharmacology(2009) 204, 37-48. This mice model may be used to assay theeffectiveness of the methods and compositions of the invention intreating schizophrenia or bipolar disorder (in particular, mania).

The efficacy of the methods and compositions of this invention intreating schizophrenia may also be assessed in animal models ofschizophrenia or bipolar disorder (in particular, mania), as well ashuman subjects with schizophrenia, using a variety of cognitive testsknown in the art, as discussed above.

Amyotrophic Lateral Sclerosis (ALS)

This invention additionally provides methods for treating ALS using theextended release levetiracetam compositions of the invention. In certainembodiments, treatment comprises improving cognitive function inpatients with ALS. In certain embodiments, treatment comprises slowingor delaying the progression of ALS. In certain embodiments, treatmentcomprises reducing the rate of decline of cognitive function associatedwith ALS. In certain embodiments, treatment comprises preventing orslowing the progression, of ALS. In certain embodiments, treatmentcomprises alleviation, amelioration or slowing the progression, of oneor more symptoms associated with ALS. In certain embodiments, thesymptom to be treated is cognitive impairment. The methods andcompositions may be used for human patients in clinical applications intreating ALS. The dose of the composition and dosage interval for themethod is, as described herein, one that is safe and efficacious inthose applications.

In addition to the degeneration of motor neurons, ALS is characterizedby neuronal degeneration in the entorhinal cortex and hippocampus,memory deficits, and neuronal hyperexcitability in different brain areassuch as the cortex.

The efficacy of the methods and compositions of this invention intreating ALS, or cognitive impairment associated with ALS, may also beassessed in animal models of ALS, as well as human subjects with ALS,using a variety of cognitive tests known in the art, as discussed above.

Cancer Therapy-Related Cognitive Impairment

This invention additionally provides methods for treating cancertherapy-related cognitive impairment using the extended releaselevetiracetam compositions of the invention. In certain embodiments,treatment comprises improving cognitive function in patients with cancertherapy-related cognitive impairment. In certain embodiments, treatmentcomprises slowing or delaying the progression of cancer therapy-relatedcognitive impairment. In certain embodiments, treatment comprisesreducing the rate of decline of cognitive function associated withcancer therapy-related cognitive impairment. In certain embodiments,treatment comprises preventing or slowing the progression, of cancertherapy-related cognitive impairment. In certain embodiments, treatmentcomprises alleviation, amelioration or slowing the progression, of oneor more symptoms associated with cancer therapy-related cognitiveimpairment. The methods and compositions may be used for human patientsin clinical applications in treating cancer therapy-related cognitiveimpairment. The dose of the composition and dosage interval for themethod is, as described herein, one that is safe and efficacious inthose applications.

Therapies that are used in cancer treatment, including chemotherapy,radiation, or combinations thereof, can cause cognitive impairment inpatients, in such functions as memory, learning and attention.Cytotoxicity and other adverse side-effects on the brain of cancertherapies are the basis for this form of cognitive impairment, which canpersist for decades. (Dietrich et al., Oncologist 13:1285-95, 2008;Soussain et al., Lancet 374:1639-51, 2009).

Cognitive impairment following cancer therapies reflects dysfunction infrontal cortical and hippocampal circuits that are essential for normalcognition. In animal models, exposure to either chemotherapy orradiation adversely affects performance on tests of cognitionspecifically dependent on these brain systems, especially thehippocampus (Kim et al., J. Radiat. Res. 49:517-526, 2008; Yang et al.,Neurobiol. Learning and Mem. 93:487-494, 2010). Thus, drugs targetingthese cortical and hippocampal systems could be neuroprotective inpatients receiving cancer therapies and efficacious in treating symptomsof cognitive impairment that may last beyond the interventions used ascancer therapies.

Animal models serve as an important resource for developing andevaluating treatments for cancer therapy-related cognitive impairment.Features that characterize cancer therapy-related cognitive impairmentin animal models typically extend to cancer therapy-related cognitiveimpairment in humans. Thus, efficacy in such animal models is expectedto be predictive of efficacy in humans. Various animal models of cancertherapy-related cognitive impairment are known in the art.

Examples of animal models of cancer therapy-related cognitive impairmentinclude treating animals with anti-neoplastic agents such ascyclophosphamide (CYP) or with radiation, e.g., ⁶⁰Co gamma-rays. (Kim etal., J. Radiat. Res. 49:517-526, 2008; Yang et al., Neurobiol. Learningand Mem. 93:487-494, 2010). The cognitive function of animal models ofcancer therapy-related cognitive impairment may then be tested withcognitive tests to assay the effectiveness of the methods andcompositions of the invention in treating cancer therapy-relatedcognitive impairment. The efficacy of the methods and compositions ofthis invention in treating cancer therapy-related cognitive impairment,as well as human subjects with cancer therapy-related cognitiveimpairment, using a variety of cognitive tests known in the art, asdiscussed above.

Parkinson's Disease (PD)

Parkinson's disease (PD) is a neurological disorder characterized by adecrease of voluntary movements. The afflicted patient has reduction ofmotor activity and slower voluntary movements compared to the normalindividual. The patient has characteristic “mask” face, a tendency tohurry while walking, bent over posture and generalized weakness of themuscles. There is a typical “lead-pipe” rigidity of passive movements.Another important feature of the disease is the tremor of theextremities occurring at rest and decreasing during movements.

Parkinson's disease, the etiology of which is unknown, belongs to agroup of the most common movement disorders named parkinsonism, whichaffects approximately one person per one thousand. These other disordersgrouped under the name of parkinsonism may result from viral infection,syphilis, arteriosclerosis and trauma and exposure to toxic chemicalsand narcotics. Nonetheless, it is believed that the inappropriate lossof synaptic stability may lead to the disruption of neuronal circuitsand to brain diseases. Whether as the result of genetics, drug use, theaging process, viral infections, or other various causes, dysfunction inneuronal communication is considered the underlying cause for manyneurologic diseases, such as PD (Myrrhe van Spronsen and Casper C.Hoogenraad. Curr Neurol. Neurosci. Rep. 2010, 10, 207-214).

Regardless of the cause of the disease, the main pathologic feature isdegeneration of dopaminergic cells in basal ganglia, especially insubstantia nigra. Due to premature death of the dopamine containingneurons in substantia nigra, the largest structure of the basal ganglia,the striatum, will have reduced input from substantia nigra resulting indecreased dopamine release. The understanding of the underlyingpathology led to the introduction of the first successful treatmentwhich can alleviate Parkinson's disease. Virtually all approaches to thetherapy of the disease are based on dopamine replacement. Drugscurrently used in the treatment can be converted into dopamine aftercrossing the blood brain barrier, or they can boost the synthesis ofdopamine and reduce its breakdown. Unfortunately, the main pathologicevent, degeneration of the cells in substantia nigra, is not helped. Thedisease continues to progress and frequently after a certain length oftime, dopamine replacement treatment will lose its effectiveness.

This invention provides methods for treating PD using the extendedrelease levetiracetam composition of the invention. In certainembodiments, treatment comprises preventing or slowing the progressionof PD. In certain embodiments, treatment comprises alleviation,amelioration, or slowing the progression of one or more symptomsassociated with PD. In certain embodiments, the symptom to be treated iscognitive impairment. For example, methods and compositions of thedisclosure can be used to improve the motor/cognitive impairmentssymptomatic of Parkinson's disease. Moreover, methods and compositionsof the disclosure may be useful for treating the memory impairmentsymptomatic of Parkinson's disease.

There are a number of animal models for PD. Exemplary animal models forPD include the reserpine model, the methamphetamine model, the6-hydroxydopamine (6-OHDA) model, the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model, the paraquat(PQ)-Maneb model, the rotenone model, the 3-nitrotyrosine model andgenetic models using transgenic mice. Transgenic models include micethat over express α-synuclein, express human mutant forms ofα-synuclein, or mice that express LRKK2 mutations. See review of thesemodels by Ranjita B. et al. (Ranjita B. et al. BioEssays 2002, 24,308-318). Additional information regarding these animal models isreadily available from Jackson Laboratories (see alsohttp://research.jax.org/grs/parkinsons.html), as well as in numerouspublications disclosing the use of these validated models.

The efficacy of the methods and compositions of this invention intreating PD, or cognitive impairment associated with PD, may be assessedin any of the above animal models of PD, as well as human subjects withPD, using a variety of cognitive tests known in the art, as discussedabove.

Autism

“Autism”; as used herein, refers to an autism spectrum disordercharacterized by a neural development disorder leading to impairedsocial interaction and communication by restricted and repetitivebehavior. “Autism Spectrum Disorder” refers to a group of developmentaldisabilities that includes: autism; Asperger syndrome; pervasivedevelopmental disorder not otherwise specified (PDD-NOS or atypicalautism); Rett syndrome; and childhood disintegrative disorder.

Autism is a neurodevelopmental disorder characterized by dysfunction inthree core behavioral dimensions: repetitive behaviors, social deficits,and cognitive deficits. The repetitive behavior domain involvescompulsive behaviors, unusual attachments to objects, rigid adherence toroutines or rituals, and repetitive motor mannerisms such asstereotypies and self-stimulatory behaviors. The social deficitdimension involves deficits in reciprocal social interactions, lack ofeye contact, diminished ability to carry on conversation, and impaireddaily interaction skills. The cognitive deficits can include languageabnormalities. Autism is a. disabling neurological disorder that affectsthousands of Americans and encompasses a number of subtypes, withvarious putative causes and few documented ameliorative treatments. Thedisorders of the autistic spectrum may be present at birth, or may havelater onset, for example, at ages two or three. There are no clear cutbiological markers for autism. Diagnosis of the disorder is made byconsidering the degree to which the child matches the behavioralsyndrome, which is characterized by poor communicative abilities,peculiarities in social and cognitive capacities, and maladaptivebehavioral patterns. The dysfunction in neuronal communication isconsidered one of the underlying causes for autism (Myrrhe van Spronsenand Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10,207-214).

This invention provides methods for treating autism using the extendedrelease levetiracetam composition of the invention. In certainembodiments, treatment comprises preventing or slowing the progressionof autism. In certain embodiments, treatment comprises alleviation,amelioration, or slowing the progression of one or more symptomsassociated with autism. In certain embodiments, the symptom to betreated is cognitive deficit. For example, methods and compositions ofthe disclosure can be used to improve the motor/cognitive deficitssymptomatic of autism.

Mental retardation

Mental retardation is a generalized disorder characterized bysignificantly impaired cognitive function and deficits in adaptivebehaviors. Mental retardation is often defined as an IntelligenceQuotient (IQ) score of less than 70. Inborn causes are among manyunderlying causes for mental retardation. The dysfunction in neuronalcommunication is also considered one of the underlying causes for mentalretardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol.Neurosei. Rep. 2010, 10, 207-214).

In some instances, mental retardation includes, but are not limited to,Down syndrome, velocariofacial syndrome, fetal alcohol syndrome, FragileX syndrome, Klinefelter's syndrome, neurofibromatosis, congenitalhypothyroidism, Williams syndrome, phenylketonuria (PKU),Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermidsyndrome, Mowat-Wilson syndrome, ciliopathy, Lowe syndrome and sideriumtype X-linked mental retardation. Down syndrome is a disorder thatincludes a combination of birth defects, including some degree of mentalretardation, characteristic facial features and, often, heart defects,increased infections, problems with vision and hearing, and other healthproblems. Fragile X syndrome is a prevalent form of inherited mentalretardation, occurring with a frequency of 1 in 4,000 males and 1 in8,000 females. The syndrome is also characterized by developmentaldelay, hyperactivity, attention deficit disorder, and autistic-likebehavior. There is no effective treatment for fragile X syndrome.

The present invention contemplates the treatment of mild mentalretardation, moderate mental retardation, severe mental retardation,profound mental retardation, and mental retardation severityunspecified. Such mental retardation may be, but is not required to be,associated with chromosomal changes, (for example Down Syndrome due totrisomy 21), heredity, pregnancy and perinatal problems, and othersevere mental disorders. This invention provides methods for treatingmental retardation using the extended release levetiracetam compositionof the invention. In certain embodiments, treatment comprises preventingor slowing the progression of mental retardation. In certainembodiments, treatment comprises alleviation, amelioration, or slowingthe progression of one or more symptoms associated with mentalretardation. In certain embodiments, the symptom to be treated iscognitive deficit/impairment. For example, methods and compositions ofthe disclosure can be used to improve the motor/cognitive impairmentssymptomatic of mental retardation.

Several animal models have been developed for mental retardation. Forexample, a knockout mouse model has been developed for Fragile Xsyndrome. Fragile X syndrome is a common form of mental retardationcaused by the absence of the FMR1 protein, FMRP. Two homologs of FMRPhave been identified, FXR1P and FXR2P. FXR2P shows high expression inbrain and testis, like FMRP. Both Fxr2 and Fmr1 knockout mice, andFmr1/Fxr2 double knockout mice are believed to be useful models formental retardation such as Fragile X syndrome. See, Bontekoe C. J. M. etal. Hum. Mol. Genet. 2002, 11 (5): 487-498. The efficacy of the methodsand compositions of this invention in treating mental retardation, orcognitive deficit/impairment associated with mental retardation, may beassessed in the these mouse models and other animal models developed formental retardation, as well as human subjects with mental retardation,using a variety of cognitive tests known in the art, as discussed above.

Compulsive Behavior (Obsessive Compulsive Disorder)

Obsessive compulsive disorder (“CCD”) is a mental condition that is mostcommonly characterized by intrusive, repetitive unwanted thoughts(obsessions) resulting in compulsive behaviors and mental acts that anindividual feels driven to perform (compulsion). Current epidemiologicaldata indicates that OCD) is the fourth most common mental disorder inthe United States. Some studies suggest the prevalence of OCD is betweenone and three percent, although the prevalence of clinically recognizedOCD is much lower, suggesting that many individuals with the disordermay not be diagnosed. Patients with OCD are often diagnosed by apsychologist, psychiatrist, or psychoanalyst according to the Diagnosticand Statistical Manual of Mental Disorders, 4th edition text revision(DSM-IV-TR) (2000) diagnostic criteria that include characteristics ofobsessions and compulsions. Characteristics of obsession include: (1)recurrent and persistent thoughts, impulses, or images that areexperienced as intrusive and that cause marked anxiety or distress; (2)the thoughts, impulses, or images are not simply excessive worries aboutreal-life problems; and (3) the person attempts to ignore or suppresssuch thoughts, impulses, or images, or to neutralize them with someother thought or action. The person recognizes that the obsessionalthoughts, impulses, or images are a product of his or her own mind, andare not based in reality. Characteristics of compulsion include: (1)repetitive behaviors or mental acts that the person feels driven toperform in response to an obsession, or according to rules that must beapplied rigidly; (2) the behaviors or mental acts are aimed atpreventing or reducing distress or preventing some dreaded event orsituation; however, these behaviors or mental acts are not actuallyconnected to the issue, or they are excessive.

Individuals with OCD typically perform tasks (or compulsion) to seekrelief from obsession-related anxiety. Repetitive behaviors such ashandwashing, counting, checking, or cleaning are often performed withthe hope of preventing obsessive thoughts or making them go away.Performing these “rituals,” however, only provides temporary relief.People with OCD may also be diagnosed with a spectrum of other mentaldisorders, such as generalized anxiety disorder, anorexia nervosa, panicattack, or schizophrenia.

The dysfunction in neuronal communication is considered one of theunderlying causes for obsession disorder (Myrrhe van Spronsen and CasperC. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214), Studiessuggest that OCD may be related to abnormal levels of a neurotransmittercalled serotonin. The first-line treatment of OCD consists of behavioraltherapy, cognitive therapy, and medications. Medications for treatmentinclude serotonin reuptake inhibitors (SRIs) such as paroxetine(Seroxat™, Paxil®, Xetanor™, ParoMerck™, Rexetin™), sertraline (Zoloft®,Stimuloton™), fluoxetine (Prozac®, Bioxetin™), escitalopram (Lexapro®),and fluvoxamine (Luvox®) as well as the tricyclic antidepressants, inparticular clomipramine (Anafranil®). Benzodiazepines are also used intreatment. As much as 40 to 60% of the patients, however, fail toadequately respond to the SRI therapy and an even greater proportion ofpatients fail to experience complete remission of their symptoms.

This invention provides methods for treating OCD using the extendedrelease levetiracetam composition of the invention. In certainembodiments, treatment comprises preventing or slowing the progressionof OCD. In certain embodiments, treatment comprises alleviation,amelioration, or slowing the progression of one or more symptomsassociated with OCD. In certain embodiments, the symptom to be treatedis cognitive deficit. For example, methods and compositions of thedisclosure can be used to treat the cognitive deficits in OCD, and/or toimprove cognitive function in patients with OCD. A quinpirole-sensitizedrat model has been developed for OCD. The compulsive checking behaviorof the quinpirole-sensitized rats is subject to interruption, which isan attribute characteristic of OCD compulsions. The efficacy of themethods and compositions of this invention in treating OCD, or cognitivedeficits associated with OCD, may be assessed in this rat model andother animal models developed for OCD, as well as human subjects withOCD, using a variety of cognitive tests known in the art, as discussedabove.

Substance Addiction

Substance addiction e.g., drug substance addiction, alcohol substanceaddiction) is a mental disorder. The substance addiction is nottriggered instantaneously upon exposure to substnace of abuse. Rather,it involves multiple, complex neural adaptations that develop withdifferent time courses ranging from hours to days to months (Kauer J. A.Nat. Rev. Neurosci. 2007 8, 844-858). The path to substance addictiongenerally begins with the voluntary use of one or more controlledsubstances, such as narcotics, barbiturates, methamphetamines, alcohol,nicotine, and any of a variety of other such controlled substances. Overtime, with extended use of the controlled substance(s), the voluntaryability to abstain from the controlled substance(s) is compromised dueto the effects of prolonged use on brain function, and thus on behavior.As such, substance addiction generally is characterized by compulsivesubstance craving, seeking and use that persist even in the face ofnegative consequences. The cravings may represent changes in theunderlying neurobiology of the patient which likely must be addressed ina meaningful way if recovery is to be obtained. Substance addiction isalso characterized in many cases by withdrawal symptoms, which for somesubstances are life threatening (e.g , alcohol, barbiturates) and inothers can result in substantial morbidity (which may include nausea,vomiting, fever, dizziness, and profuse sweating), distress, anddecreased ability to obtain recovery. For example, alcoholism, alsoknown as alcohol dependence, is one such substance addiction. Alcoholismis primarily characterized by four symptoms, which include cravings,loss of control, physical dependence and tolerance. These symptoms alsomay characterize substance addictions to other controlled substances.The craving for alcohol, as well as other controlled substances, oftenis as strong as the need for food or water. Thus, an alcoholic maycontinue to drink despite serious family, health and/or legalramifications.

Recent work exploring the effects of abusing alcohol, centralstimulants, and opiates on the central nervous system (CNS) havedemonstrated a variety of adverse effects related to mental health,including substance-induced impairments in cognition. See, Nyberg F.Cognitive Impairments in Drug Addicts, Chapter 9. In severallaboratories and clinics substantial damages of brain function are seento result from these drugs. Among the harmful effects of the abusingdrugs on brain are those contributing to accelerated obsolescence. Anobservation that has received special attention during recent years isthat chronic drug users display pronounced impairment in brain areasassociated with executive and memory function. A remarkedneuroadaptation caused by addictive drugs, such as alcohol, centralstimulants and opiates involves diminished neurogenesis in thesubgranular zone (SGZ) of the hippocampus. Indeed, it has been proposedthat decreased adult neurogenesis in the SGZ could modify thehippocampal function in such a way that it contributes to relapse and amaintained addictive behavior. It also raises the possibility thatdecreased neurogenesis may contribute to cognitive deficits elicited bythese abusing drugs.

This invention provides methods for treating substance addiction usingthe extended release levetiracetam composition of the invention. Incertain embodiments, treatment comprises preventing or slowing theprogression of substance addiction. In certain embodiments, treatmentcomprises alleviation, amelioration, or slowing the progression of oneor more symptoms associated with substance addiction. In certainembodiments, the symptom to be treated is cognitive impairment. Forexample, methods and compositions of the disclosure can be used to treatthe cognitive impairment and/or to improve cognitive function inpatients with substance addiction.

Several animal models have been developed to study substance addiction.For example, a genetically selected Marchigian Sardinianalcohol-preferring (msP) rat models is developed to study theneurobiology of alcoholism. See, Ciccocioppo R. et al. Substanceaddiction Biology 2006, 11, 339-355. The efficacy of the methods andcompositions of this invention in treating substance addiction, orcognitive impairment associated with substance addiction, may also beassessed in animal models of substance addiction, as well as humansubjects with substance addiction, using a variety of cognitive testsknown in the art, as discussed above.

Appropriate methods of administering the extended release compositionsof the invention will also depend, for example, on the age of thesubject, whether the subject is active or inactive at the time ofadministering, whether the subject is cognitively impaired at the timeof administering, or the extent of the impairment. In some embodiments,the extended release levetiracetam composition of the invention isadministered orally, e.g., to a subject by ingestion. In someembodiments, the orally administered composition is administered using adevice for extended release.

It will be understood by one of ordinary skill in the art that thecompositions and methods described herein may be adapted and modified asis appropriate for the application being addressed and that thecompositions and methods described herein may be employed in othersuitable applications, and that such other additions and modificationswill not depart from the scope hereof.

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the embodiments which followthereafter.

EXAMPLES Example 1 A Process for Making Extended Release CompositionsComprising 190 mg of Levetiracetam

TABLE 1 Tablet A Tablet B Tablet C (Mg/ (Mg/ (Mg/ IngredientFunctionality Tablet) Tablet) Tablet) Levetiracetam Base API 190.0 190.0190.0 Hypromellose Matrix 300.0 — — (Methocel ™ K15M Former CR)Hypromellose Matrix — 300.0 300.0 (Methocel ™ K100M Former Premium CR)Colloidal Silicon Glidant 1.2 1.2 1.2 Dioxide Silicified Micro- Diluent102.8 102.8 — crystalline Cellulose ProSolv ™ HD90 Encompress, Diluent —— 102.8 Anhydrous dicalcium phosphate Magnesium Stearate Lubricant 6.06.0 6.0 Total 600 600 600

Three extended release tablets A, B, and C comprising 190 mg oflevetiracetam as shown in Table 1 are manufactured following the processexemplified in the flow diagram of FIG. 1. The process exemplified inthe flow diagram of FIG. 9 could also be used. In brief, SilicifiedMicrocrystalline Cellulose ProSolv™ SMCC HD90 (or Encompress, Anhydrousdicalcium phosphate) is sifted through deagglomerate #30 U.S. meshsieve, and then blended with Colloidal Silicon Dioxide (16 qt V-shellblender; 75 rev±5 rev). The blended sample then goes through Round 1601Impeller (2A024R screen). 190 mg of levetiracetam and hypromellose 2208(Methocel™ K15M Premium CR) (or Methocel™ K100M Premium CR) are alsosifted through deagglomerate #30 U.S. mesh sieve, and then blended in a1 ft³ Slant Cone Blender (250 rev±5 rev) with the ground SilicifiedMicrocrystalline Cellulose ProSolv™ HD90 and Colloidal Silicon Dioxide.This blended sample then goes through Round 1601 Impeller (2A024Rscreen) and then is blended in a 1 ft³ Slant Cone Blender (125 rev±5rev) with sieved Magnesium Stearate (HyQual®) (sieved throughdeagglomerate #30 U.S. mesh sieve). The blended samples are compressedinto tablets. Optionally, the tablets are further film coated with ahypromellose-based (HPMC-based) coating, such as Opadry® complete filmcoating system.

Example 2 Dissolution Profile of Extended Release CompositionsComprising 190 mg of Levetiracetam

Table 2 below shows the dissolution profile for the 190 mg levetiracetamextended release Tablet A of Table 1.

TABLE 2 Test Results (Time: Percentages of dissolution) Dissolution 1hr: 29% 3 hr: 51% 12 hr: 92% When extended release Tablet A is placed in variety of EtOHconcentrations in 0.1N HCL, no dose dumping is observed.

Example 3 A Process for Making Extended Release Compositions Comprising220 mg of Levetiracetam

TABLE 3 Tablet D Tablet E Ingredient Functionality (Mg/Tablet)(Mg/Tablet) Levetiracetam API 220.0 220.0 Hypromellose (Methocel ™Matrix Former 280.0 347.5 K15M CR) Colloidal Silicon Dioxide Glidant 1.21.4 Silicified Microcrystalline Diluent 92.8 119.2 Cellulose ProSolv ™HD90 Magnesium Stearate Lubricant 6.0 6.7 Total 600 695

Two extended release tablets D and E comprising 220 mg of levetiracetamas shown in Table 3 are manufactured following the process exemplifiedin the flow diagram of FIG. 1. The process exemplified in the flowdiagram of FIG. 9 could also be used. In brief, SilicifiedMicrocrystalline Cellulose ProSolv™ SMCC HD90 (or Encompress, Anhydrousdicalcium phosphate) is sifted through deagglomerate #30 U.S. meshsieve, and then blended with Colloidal Silicon Dioxide (16 qt V-shellblender; 75 rev±5 rev). The blended sample then goes through Round 1601Impeller (2A024R screen). 220 mg of levetiracetam and hypromellose 2208(Methocel™ K15M Premium CR) (or Methocel™ K100M Premium CR) are alsosifted through deagglomerate #30 U.S. mesh sieve, and then blended in a1 ft³ Slant Cone Blender (250 rev±5 rev) with the ground SilicifiedMicrocrystalline Cellulose ProSolv™ HD90 and Colloidal Silicon Dioxide.This blended sample then goes through Round 1601 Impeller (2A024Rscreen) and then is blended in a 1 ft³ Slant Cone Blender (125 rev±5rev) with sieved Magnesium Stearate (HyQual®) (sieved throughdeagglomerate #30 U.S. mesh sieve). The blended samples are compressedinto tablets. Optionally, the tablets are further film coated with ahypromellose-based (HPMC-based) coating, such as Opadry® complete filmcoating system.

Example 4 Dissolution Profile of Extended Release CompositionsComprising 220 mg of Levetiracetam

Table 4 below shows the dissolution profile for the 220 mg levetiracetamextended release Tablet D of Table 3.

TABLE 4 Test Results (Time: Percentages of dissolution) Dissolution 1hr: 28% 3 hr: 49% 12 hr: 91% When extended release Tablet D is placed in variety of EtOHconcentrations in 0.1N HCL, no dose dumping is observed.

Example 5 Evaluation of Extended Release Compositions of 190 mgLevetiracetam on Pharmacokinetics in Dogs Overview

The purpose of this study is to collect samples for investigating thepharmacokinetics of novel extended release formulations of levetiracetam(190 mg) in male dogs following oral administration. Table 1 provides adescription of the three formulations utilized in this study (190 mgTablets A, B, and C).

Animals

Thirty non-naïve male purebred beagle dogs from the Covance Stock colonyare used in these studies. The animals are acclimated to studyconditions for approximately three days prior to dose administration. Atdosing, the animals weigh 8.4 to 12.8 kg and are 1 to 2 years of age.All animals are housed in individual, stainless steel cages duringacclimation and the test period, except during periods of commingling inaccordance with Covance SOPs. Certified Harlan Teklad 2021, 21% ProteinDog Diet is provided ad libitum unless otherwise specified for doseadministration. Water is provided fresh daily, ad libitum. Environmentalcontrols for the animal room are set to maintain a temperature of 68 to79° F., a relative humidity of 50±20%, and a 12-hour light/12-hour darkcycle. As necessary, the 12-hour dark cycle is interrupted toaccommodate study procedures.

Study Design

Five groups of dogs (N=6 per group) are utilized in this study. Animmediate release 250 mg levetiracetam (LEV IR) tablet is administeredas a 250 mg oral BID regimen (a total dose of 500). An extended release500 mg levetiracetam tablet (LEV XR) is administered as a single oraldose of 500 mg. Tablets A, B, and C are administered as single oraldoses of 190 mg. Plasma pharmacokinetic samples are collected atpre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 13 (collecting only LEV IR), 18,24, and 48 hours post dose. For LEV IR, the 12-hour blood sample iscollected just prior to administration of the second dose.

TABLE 5 Overview of Study Design Number of Target Dose Male Test DoseLevel Group Animals Article Route (mg/tablet) 1 6 LEV - IR Oral Tablet250 2 6 LEV - XR Oral Tablet 500 3 6 Tablet A Oral Tablet 190 4 6 TabletB Oral Tablet 190 5 6 Tablet C Oral Tablet 190 IR Immediate release. XRExtended release. Notes: Animals in Group 1 receive two 250 mg tablets,approximately 12 hours apart (500 mg total dose). Animals in Groups 2through 5 receive a single tablet.

Analytical Methods

Sample analysis is performed using a Covance-owned generic method andanalog internal standard. The method is adjusted as appropriate for thespecific test article used on study. Data collection and chromatographicinterpretation is performed in Analyst and the Laboratory InformationManagement System (LIMS) used on study is Watson.

Absorption and Plasma Levels

LEV IR vs. LEV XR: LEV IR is administered as a 250 mg oral BID regimen(total daily dose of 500 mg). LEV XR is administered as a single oraldose of 500 mg. Based on mean plasma C. and AUC_(0-inf), the overallexposure of dogs to levetiracetam is similar with both formulations(FIG. 2, Table 6). The plasma T_(max) is earlier with the IR formulation(range 0.25-2.00 h; mean 1.00 h) than with the XR formulation (range2.00-4.00 h; mean 3.33 h). The apparent elimination half-life oflevetiracetam in plasma averages 3.50±0.273 h and 4.23±0.590 h with theLEV IR and LEV XR formulations, respectively.

190 mg Tablets A, B, and C: 190 mg Tablets A, B, and C of Table 1 areadministered as single oral doses of 190 mg. The highest exposure tolevetiracetam is achieved with Tablet A (FIG. 2, Table 6); plasmaC_(max) and AUC_(0-inf) averaged 8650±1440 ng/mL and 90000±27200ng·h/mL, respectively. The plasma T_(max) generally range from 2.00 to4.00 hours. The apparent elimination half-life of levetiracetam inplasma average 4.15±1.26 h.

TABLE 6 Pharmacokinetic parameters in plasma collected from male dogsfollowing oral administration of levetiracetam Animal C_(max) C_(max)/DT_(max) AUC_(0-t) AUC_(0-inf) AUC_(0-inf)/D t_(1/2) Number Group (ng/mL)((ng/mL)/mg) (h) (h · ng/mL) (h · ng/mL) ((h · ng/mL)/mg) (h) 250 mg BID(LEV - IR) 112515 1 29200 58.4 0.50 247000 247000 493 3.32 113624 123200 46.4 0.25 237000 237000 474 3.45 113626 1 31400 62.8 0.25 302000302000 604 3.44 113648 1 38100 76.2 2.00 277000 277000 554 3.15 113627 124300 48.6 2.00 280000 280000 560 3.83 113614 1 24500 49.0 1.00 214000214000 428 3.82 Mean 28500 56.9 1.00 259000 259000 519 3.50 SD 5710 11.40.822 32400 32400 64.8 0.273 500 mg (LEV - XR) 113637 2 36900 73.8 4.00218000 218000 436 3.73 113643 2 25000 50.0 2.00 265000 265000 531 5.19113646 2 31600 63.2 4.00 302000 302000 604 4.16 112513 2 35400 70.8 2.00317000 317000 634 3.74 113638 2 24900 49.8 4.00 230000 230000 460 4.69113615 2 44300 88.6 4.00 287000 287000 574 3.89 Mean 33000 66.0 3.33270000 270000 540 4.23 SD 7490 15.0 1.03 39600 39600 79.1 0.590 190 mg(Tablet A) 112417 3 9900 52.1 2.00 122000 122000 644 3.51 113636 3 1010053.2 4.00 108000 108000 571 3.94 113616 3 7740 40.7 2.00 125000 NR NR NR113613 3 7310 38.5 2.00 53100 53100 280 6.36 113618 3 7000 36.8 2.0075600 75600 398 3.23 112516 3 9820 51.7 4.00 90600 90600 477 3.69 Mean8650 45.5 2.67 95900 90000 474 4.15 SD 1440 7.58 1.03 28200 27200 1431.26 AUC_(0-t) Area under the plasma concentration-time curve up to thelast sampling time with measurable concentrations. AUC_(0-inf) Areaunder the plasma concentration-time curve up to infinity. AUC_(0-inf)/DDose adjusted area under the plasma concentration-time curve up toinfinity. C_(max) Maximum plasma concentration. C_(max)/D Dose adjustedmaximum plasma concentration. h Hours. IR Immediate release. NR Notreported. SD Standard deviation. T_(max) Time to maximum concentration.t_(1/2) Observed elimination half-life. XR Extended release.

The highest overall exposure of levetiracetam in dogs is achieved withthe LEV XR and LEV IR formulations. Of the 190 mg Tablets A, B, and C,the highest overall exposure of levetiracetam in dogs is achieved withthe 190 mg Tablet A. Based on the mean dose-adjusted plasma C_(max) andAUC_(0-inf) values, the levetiracetam exposure achieved with the 190 mgTablet A is approximately 69% and 88%, respectively, of the exposureachieved with the LEV XR formulation, and 80% and 91%, respectively, ofthe exposure achieved with the LEV IR formulation.

Example 6 Evaluation of Extended Release Compositions of 220 mgLevetiracetam on Pharmacokinetics in Dogs Overview

The purpose of this study is to collect samples for investigating thepharmacokinetics of novel extended release formulations of levetiracetam(220 mg) in male dogs following oral administration. Table 3 provides adescription of the two formulations utilized in this study (220 mgTablets D and E).

Animals

Eighteen non-naïve male purebred beagle dogs from the Covance Stockcolony are used in these studies. The animals are acclimated to studyconditions for approximately three days prior to dose administration. Atdosing, the animals weigh 7.6 to 11.7 kg and are approximately 1 year ofage. All animals are housed in individual, stainless steel cages duringacclimation and the test period, except during periods of commingling inaccordance with Covance SOPs. Certified Harlan Teklad 2021, 21% ProteinDog Diet is provided ad libitum unless otherwise specified for doseadministration. Water is provided fresh daily, ad libitum. Environmentalcontrols for the animal room are set to maintain a temperature of 68 to79° F., a relative humidity of 50±20%, and a 12-hour light/12-hour darkcycle. As necessary, the 12-hour dark cycle is interrupted toaccommodate study procedures.

Study Design

Three groups of dogs (N=6 per group) are utilized in this study. LEV XRis administered as a single oral dose of 500 mg. 220 mg Tablets D and Eare administered as single oral doses of 220 mg. Plasma pharmacokineticsamples are collected at pre-dose (i.e., 0), 0.25, 0.5, 1, 2, 4, 6, 8,12, 18, 24, and 48 hours post dose. See Table 7.

TABLE 7 Overview of Study Design Number of Target Dose Male Test DoseLevel Group Animals Article Route (mg/tablet) 1 6 LEV-XR Oral Tablet 5002 6 Tablet D Oral Tablet 220 3 6 Tablet E Oral Tablet 220 XR ExtendedRelease. Note: Animals received a single tablet.

Analytical Methods

Sample analysis is performed using a Covance-owned generic method andanalog internal standard. The method is adjusted as appropriate for thespecific test article used on study. Data collection and chromatographicinterpretation are performed in Analyst and the Laboratory InformationManagement System (LIMS) used on study is Watson.

Absorption and Plasma Levels

LEV-XR is administered as a single oral tablet dose of 500 mg; the 220mg Tablets D and E are each administered as single oral tablet doses of220 mg. Based on mean dose-adjusted plasma C_(max) and AUC_(0-t), theoverall exposure of dogs to levetiracetam is similar with the LEV-XR andthe 220 mg Tablet D formulations (FIG. 3, Table 8).

LEV XR vs 220 mg Tablets

The plasma C_(max) and AUC_(0-inf) for the 220 mg Tablet D average10900±2540 ng/mL and 110000±23000 ng·h/mL, respectively. The plasmaT_(max) generally ranges from 2.00 to 6.00 hours. The apparentelimination half-life of levetiracetam in plasma averages 4.41±0.06 h.The mean dose-adjusted plasma C_(max) values are 46.6±7.37 and 49.3±11.5ng/mL for the LEV-XR and the 220 mg Tablet D respectively. Thedose-adjusted plasma AUC_(0-t) values are 452±67.2 and 499±104 ng·h/mLfor the LEV-XR and the 220 mg Tablet D, respectively.

The plasma T_(max) is similar for LEV XR and the 220 mg Tablet D(LEV-XR: range 1.0-3.6 h; mean 1.6 h; the 220 mg Tablet D: range 2.0-6.0h; mean 2.7 h). The apparent elimination half-life of levetiracetam inplasma averages 5.16±1.44 h and 4.41±0.614 h with the LEV-XR and the 220mg Tablet D formulations, respectively.

TABLE 8 Pharmacokinetic parameters in plasma collected from male dogsfollowing oral administration of Levetiracetam Dose Subject C_(max)C_(max)/D T_(max) AUC_(0-t) AUC_(0-t)/D AUC_(0-inf) t_(1/2) Group (mg)No. (ng/mL) (ng/mL)/mg (h) (ng · h/mL) (ng · h/mL)/mg (ng · h/mL) (h)500 mg (LEV - XR) 1 500 113637 25600 51.2 1.0 259000 518 259000 3.75 1500 113638 23700 47.4 3.6 201000 402 201000 7.17 1 500 113639 28800 57.61.0 263000 526 263000 5.21 1 500 113641 19500 39.0 1.0 192000 384 1920006.35 1 500 113642 19100 38.2 2.0 195000 390 196000 5.01 1 500 11364723100 46.2 1.0 247000 494 247000 3.44 N 6 6 6 6 6 6 6 Mean 23300 46.61.6 226000 452 226000 5.16 SD 3680 7.37 1.1 33500 67.2 33400 1.44 CV %15.8 15.8 66.1 14.8 14.9 14.8 28.0 220 mg (Tablet D) 2 220 113700 1530069.5 6.0 142000 645 142000 4.65 2 220 113814 10400 47.3 2.0 108000 491108000 3.91 2 220 113817 11400 51.8 2.0 130000 591 NR NR 2 220 11383210000 45.5 2.0 104000 473 104000 3.74 2 220 114110 10500 47.7 2.0 96100437 96200 5.27 2 220 114111 7520 34.2 2.0 79000 359 79000 4.50 N 6 6 6 66 5 5 Mean 10900 49.3 2.7 110000 499 106000 4.41 SD 2540 11.5 1.6 23000104 23200 0.614 CV % 23.4 23.4 61.2 20.9 20.8 21.9 13.9 AUC_(0-t) Areaunder the plasma concentration-time curve up to the last sampling timewith measurable concentrations. AUC_(0-inf) Area under the plasmaconcentration-time curve up to infinity. AUC_(0-inf)/D Dose adjustedarea under the plasma concentration-time curve up to infinity. C_(max)Maximum plasma concentration. C_(max)/D Dose adjusted maximum plasmaconcentration. CV % Coefficient of variation. h Hours. N Number ofanimals. NR Not reported due to ill-defined terminal phase. SD Standarddeviation. T_(max) Time to maximum concentration. t_(1/2) Observedelimination half-life.

Based on the mean dose-adjusted plasma C_(max) and AUC_(0-t) values, thelevetiracetam exposure achieved with the 220 mg Tablet D formulation isapproximately 107% and 110%, respectively, of the exposure achieved withthe LEV-XR formulation.

Example 7 Phase I Food Effect Study of Extended Release Compositions of190 mg and 220 mg Levetiracetam

This example describes a two-group, single-dose, two-period, two-waycrossover, food-effect study of two extended release levetiracetamformulations, i.e., the 190 mg Tablet A of Table 1 and the 220 mg TabletD of Table 3.

Objective

The objective of this study is to assess the effect of food on the rateand extent of absorption of two extended release levetiracetamformulations, i.e., the 190 mg Tablet A of Table 1 and the 220 mg TabletD of Table 3.

Steady state formulation goals: The preferred range goal is establishedbased on aMCI phase II human study: between 2.9 and 4.4 μg/mL. Theacceptable range goal is established based on Aged-Impaired (AI) ratsand aMCI phase II human study: between 1.9 and 4.4 μg/mL. See FIG. 6.

Study Design

This is an open label, randomized, two-group, single-dose, two-periodcrossover, food-effect study. Fifty-six (56) healthy subjects areenrolled. Subjects who successfully complete the screening process checkinto the research center the evening before first dose. Subjects whocontinue to meet inclusion/exclusion criteria the morning of dose areassigned a subject number, based on the order in which they successfullycomplete the required screening process and procedures. Dosing days areseparated by a washout period of at least 7 days.

Subjects are randomly assigned to one of two groups:

-   -   Group 1: Subjects (n=28) received extended-release Tablet A of        Table 1 (190 mg).    -   Treatment A: Tablet A

Dose=1×190 mg tablet, orally administered under fasted conditions

-   -   Treatment B: Tablet A

Dose=1×190 mg tablet, orally administered under fed conditions

-   -   Group 2: Subjects (n=28) received extended-release Tablet D of        Table 3 (220 mg).    -   Treatment A: Tablet D

Dose=1×220 mg tablet, orally administered under fasted conditions

-   -   Treatment B: Tablet D

Dose=1×220 mg tablet, orally administered under fed conditions

Fed treatment: Following an overnight fast of at least 10 hours,subjects began consuming a Food and Drug Administration (FDA) standardhigh-calorie, high-fat breakfast meal 30 minutes prior to administrationof the study drug.

Fasted treatment: Subjects are dosed after an overnight fast of at least10 hours.

Each drug administration is separated by a washout period of at least 7days.

Each dose is orally administered along with approximately 240 mL (8 fl.oz.) of room temperature water. After dosing, no food is allowed until 4hours postdose. Except for the 240 mL of room temperature water providedwith the dose, no water might be consumed for 1 hour prior through 1hour after dose. Water consumption followed the guidelines in Section5.4.2. With the exception of the FDA standard high-calorie, high-fatbreakfast meal served during the fed treatment period, meals are thesame and scheduled at approximately the same times relative to dose foreach study period.

Subjects who withdraw from the study are not replaced.

Clinical Procedures Summary

During each study period, 6 mL blood samples are obtained prior to eachdosing and following each dose at selected times through 24 hourspost-dose. A total of 34 pharmacokinetic blood samples are to becollected from each subject, 17 samples in each study period. Inaddition, blood is drawn and urine is collected for clinical laboratorytesting at screening and study exit.

In each study period, subjects are admitted to the study unit in theevening prior to the scheduled dose. Subjects are confined to theresearch center during each study period until completion of the 24-hourblood collection and other study procedures.

Procedures for Collecting Samples for Pharmacokinetic Analysis

Blood samples (1×6 mL) are collected in vacutainer tubes containingK₂-EDTA as a preservative at pre-dose (0) and at 1.0, 2.0, 3.0, 4.0,4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10, 12, 18, and 24 hours afterdosing.

Bioanalytical Summary

Plasma samples are analyzed for levetiracetam using a validated LC-MS-MSprocedure. The method is validated for a range of 0.0500 to 30.0 μg/mLfor levetiracetam, based on the analysis of 0.200 mL of human EDTAplasma. Data are stored in Watson Laboratory Information ManagementSystem (LIMS; Version 7.2.0.03, Thermo Fisher Scientific).

Pharmacokinetic Analysis

Data are analyzed by noncompartmental methods in WinNonlin.Concentration-time data that are below the limit of quantification (BLQ)are treated as zero in the data summarization and descriptivestatistics. In the pharmacokinetic analysis, BLQ concentrations aretreated as zero from time-zero up to the time at which the firstquantifiable concentration is observed; embedded and/or terminal BLQconcentrations are treated as “missing”. Actual sample times are usedfor all pharmacokinetic and statistical analyses.

The following pharmacokinetic parameters are calculated: peakconcentration in plasma (C_(max)), time to peak concentration (T_(max)),elimination rate constant (λ_(z)), terminal half-life (T_(1/2)), areaunder the concentration-time curve from time-zero to the time of thelast quantifiable concentration (AUC_(last)), and area under the plasmaconcentration time curve from time-zero extrapolated to infinity(AUC_(inf)). Additionally, C_(max), AUC_(last), and AUC_(inf) aredose-normalized.

Analysis of variance (ANOVA) and the Schuirmann's two one-sided t-testprocedures at the 5% significance level are applied to thelog-transformed pharmacokinetic exposure parameters, C_(max),AUC_(last), and AUC_(inf). The 90% confidence interval for the ratio ofthe geometric means (Test/Reference) is calculated. A lack of foodeffect is declared if the lower and upper confidence intervals of thelog-transformed parameters are within 80% to 125% (190 mg Tablet A Fedvs. 190 mg Tablet A Fasted; 220 mg Tablet D Fed vs. 220 mg Tablet DFasted). Additionally, the dose-normalized C_(max), AUC_(last), andAUC_(inf) are compared within fasted and fed conditions to determinedose-proportionality. Dose-proportionality is concluded if the lower andupper confidence intervals of the dose-normalized, log-transformedparameters are within 80% to 125% (220 mg Tablet D Fasted vs. 190 mgTablet A Fasted; 220 mg Tablet D Fed vs. 190 mg Tablet A Fed)

Results

Data from 55 subjects for Group 1 and 54 subjects for Group 2 areincluded in the pharmacokinetic and statistical analyses. Meanconcentration-time data are shown in Tables 9 and 10 and in FIGS. 4 and5. Results of the pharmacokinetic and statistical analyses are shownbelow in Tables 9-15.

Conclusions Food-Effect:

The 90% confidence intervals for the log-transformed exposure parametersC_(max), AUC_(last), and AUC_(inf) are within the 80% to 125% range forthe 190 mg and 220 mg doses. The presence of food does not alter thepharmacokinetics of the 190 mg and 220 mg levetiracetam doses.

Dose Proportionality:

The 90% confidence intervals for the dose-normalized log-transformedexposure parameters C_(max)/D, AUC_(last)/D, and AUC_(inf)/D are withinthe 80% to 125% range for fed and fasted conditions. Levetiracetamexposure, as measured by C_(max)/D, AUC_(last)/D, and AUC_(inf)/D,increase proportionately from 190 mg (Tablet A) to 220 mg (Tablet D).

Steady State Modeling

According to the steady state modeling of PK profile for the 190 mgTablet A, it meets the acceptable range goal, i.e., between 1.9 and 4.4μg/ml. See FIG. 7.

According to the steady state modeling of PK profile for the 220 mgTablet D, it meets the preferred range goal, i.e., between 2.9 and 4.4μg/ml. See FIG. 8.

TABLE 9 Levetiracetam Concentration-Time Data after Administration ofExtended-Release Tablet A, 190 mg under Fasted Conditions (Group1/Treatment A) and Extended-Release Tablet A, 190 mg under FedConditions (Group 1/Treatment B) Group 1/Treatment A: Group 1/TreatmentB: 190 mg Tablet A, Fasted 190 mg Tablet A, Fed Time Mean SD CV Mean SDCV (h) n (μg/mL) (μg/mL) (%) n (μg/mL) (μg/mL) (%) 0.00 28 0.00 0.00 NC27 0.00 0.00 NC 1.00 28 1.46 0.450 30.76 27 0.665 0.351 52.82 2.00 281.96 0.535 27.21 27 1.41 0.454 32.20 3.00 28 2.11 0.548 25.93 27 1.860.391 21.03 4.00 28 2.15 0.569 26.53 27 2.19 0.443 20.25 4.50 28 2.160.549 25.42 27 2.27 0.469 20.70 5.00 28 2.11 0.508 24.08 27 2.34 0.50021.35 5.50 28 2.08 0.497 23.91 27 2.34 0.519 22.15 6.00 28 2.06 0.44521.61 27 2.38 0.514 21.58 6.50 28 2.02 0.445 22.07 27 2.39 0.516 21.577.00 28 1.99 0.437 21.97 27 2.36 0.472 20.04 8.00 28 1.94 0.451 23.20 272.34 0.517 22.13 9.00 28 1.86 0.440 23.64 27 2.30 0.543 23.64 10.00 281.81 0.464 25.58 27 2.24 0.568 25.41 12.00 28 1.65 0.402 24.42 27 1.980.471 23.74 18.00 28 1.23 0.339 27.62 27 1.24 0.306 24.63 24.00 28 0.8880.272 30.68 27 0.783 0.212 27.07 32.00 28 0.431 0.140 32.52 27 0.3420.0991 29.00 48.00 27 0.112 0.0517 46.22 27 0.0798 0.0442 55.39 Note:Plasma samples analyzed using a bioanalytical method with a validatedrange 0.0500 to 30.0 μg/mL; concentrations reported in μg/mL to 3significant figures; concentrations below limit of quantification set tozero (0.00 μg/mL) in the data summarization NC = Not calculated

TABLE 10 Levetiracetam Concentration-Time Data after Administration ofExtended-Release Tablet D, 220 mg under Fasted Conditions (Group2/Treatment A) and Extended-Release Tablet D, 220 mg under FedConditions (Group 2/Treatment B) Group 2/Treatment A: Group 2/TreatmentB: 220 mg Tablet D, Fasted 220 mg Tablet D, Fed Time Mean SD CV Mean SDCV (h) n (μg/mL) (μg/mL) (%) n (μg/mL) (μg/mL) (%) 0.00 26 0.00 0.00 NC28 0.00 0.00 NC 1.00 26 1.94 0.619 31.91 28 0.911 0.681 74.77 2.00 262.53 0.645 25.53 28 1.61 0.636 39.41 3.00 26 2.80 0.618 22.08 28 2.160.560 25.89 4.00 26 2.86 0.596 20.83 28 2.49 0.558 22.36 4.50 26 2.830.553 19.57 28 2.65 0.506 19.07 5.00 26 2.73 0.501 18.33 28 2.78 0.45416.35 5.50 26 2.70 0.499 18.47 28 2.87 0.474 16.49 6.00 26 2.64 0.48718.44 28 2.93 0.448 15.32 6.50 26 2.58 0.444 17.23 28 2.94 0.532 18.077.00 26 2.48 0.444 17.88 28 2.96 0.471 15.92 8.00 26 2.41 0.444 18.44 282.88 0.456 15.82 9.00 26 2.26 0.428 18.93 28 2.83 0.523 18.47 10.00 262.22 0.409 18.45 28 2.74 0.587 21.45 12.00 26 2.04 0.382 18.68 28 2.450.678 27.69 18.00 26 1.43 0.299 20.95 28 1.44 0.373 25.90 24.00 26 0.9980.243 24.39 28 0.873 0.261 29.87 32.00 26 0.472 0.138 29.17 28 0.3820.139 36.41 48.00 26 0.116 0.0442 38.18 28 0.0913 0.0557 61.00 Note:Plasma samples analyzed using a bioanalytical method with a validatedrange 0.0500 to 30.0 μg/mL; concentrations reported in μg/mL to 3significant figures; concentrations below limit of quantification set tozero (0.00 μg/mL) in the data summarization NC = Not calculated

TABLE 11 Pharmacokinetic Parameters of Levetiracetam Group 1/TreatmentA: Group 1/Treatment B: 190 mg Tablet A, Fasted 190 mg Tablet A, FedParameter n Mean SD CV % n Mean SD CV % T_(max) (h) 28 4.39 2.05 46.7127 6.93 1.97 28.50 C_(max) (μg/mL) 28 2.31 0.505 21.83 27 2.53 0.52820.86 Cmax/D 28 0.0122 0.00266 21.83 27 0.0133 0.00278 20.86 (μg/mL/mg)AUC_(last) 28 46.40 11.44 24.66 27 46.53 9.352 20.10 (h*μg/mL) AUClast/D28 0.2442 0.06024 24.66 27 0.2449 0.04922 20.10 (h*μg/mL/mg) AUC_(inf)28 47.93 11.63 24.25 27 47.81 9.451 19.77 (h*μg/mL) AUCinf/D 28 0.25230.06119 24.25 27 0.2516 0.04974 19.77 (h*μg/mL/mg) AUC_(Extrap) (%) 283.29 2.52 76.75 27 2.72 1.40 51.57 λ_(z) (h⁻¹) 28 0.0873 0.0114 13.11 270.0911 0.0096 10.50 T_(1/2) (h) 28 8.09 1.17 14.50 27 7.70 0.88 11.39T_(last) (h) 28 46.82 4.19 8.94 27 45.64 5.80 12.70 C_(last) (μg/mL) 280.125 0.0661 52.74 27 0.115 0.0605 52.46 Group 2/Treatment A: Group2/Treatment B: 220 mg Tablet D, Fasted 220 mg Tablet D, Fed Parameter nMean SD CV % n Mean SD CV % T_(max) (h) 26 4.04 1.25 30.91 28 6.64 1.8327.55 C_(max) (μg/mL) 26 3.02 0.569 18.88 28 3.16 0.623 19.73 Cmax/D 260.0137 0.00259 18.88 28 0.0143 0.00283 19.73 (μg/mL/mg) AUC_(last) 2656.33 10.42 18.49 28 55.27 10.35 18.72 (h*μg/mL) AUClast/D 26 0.25600.04734 18.49 28 0.2512 0.04702 18.72 (h*μg/mL/mg) AUC_(inf) 26 57.6810.67 18.50 28 56.63 10.53 18.59 (h*μg/mL) AUCinf/D 26 0.2622 0.0485018.50 28 0.2574 0.04784 18.59 (h*μg/mL/mg) AUC_(Extrap) (%) 26 2.35 1.1047.03 28 2.42 1.19 48.97 λ_(z) (h⁻¹) 26 0.0905 0.0123 13.63 28 0.09330.0126 13.50 T_(1/2) (h) 26 7.81 1.14 14.59 28 7.56 1.01 13.32 T_(last)(h) 26 48.01 0.06 0.13 28 45.73 5.71 12.48 C_(last) (μg/mL) 26 0.1160.0442 38.18 28 0.124 0.0640 51.46

TABLE 12 Statistical Analysis of the Natural Log-Transformed SystemicExposure Parameters of Levetiracetam Comparing Extended-Release TabletA, 190 mg under Fed Conditions (Treatment B1) to Extended-Release TabletA, 190 mg under Fasted Conditions (Treatment A1) in Group 1 DependentGeometric Mean^(a) Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref(Test/Ref) Lower Upper Power CV % ln(C_(max)) 2.4777 2.2968 107.88103.32 112.63 1.0000 9.29 ln(AUC_(last)) 45.6972 45.6427 100.12 95.44105.02 1.0000 10.31 ln(AUC_(inf)) 46.9703 47.0059 99.92 95.38 104.681.0000 10.02 ^(a)Geometric Mean for 190 mg Tablet A, Fed (Test-B1) and190 mg Tablet A, Fasted (Ref-A1) based on Least Squares Mean oflog-transformed parameter values ^(b)Ratio(%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 13 Statistical Analysis of the Natural Log-Transformed SystemicExposure Parameters of Levetiracetam Comparing Extended-Release TabletD, 220 mg under Fed Conditions (Treatment B2) to Extended-Release TabletD, 220 mg under Fasted Conditions (Treatment A2) in Group 2 DependentGeometric Mean^(a) Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref(Test/Ref) Lower Upper Power CV % ln(C_(max)) 3.1117 2.9660 104.91100.32 109.72 1.0000 9.43 ln(AUC_(last)) 54.5598 55.6286 98.08 94.03102.30 1.0000 8.86 ln(AUC_(inf)) 55.9406 56.9747 98.18 94.21 102.331.0000 8.71 ^(a)Geometric Mean for 220 mg Tablet D, Fed (Test-B2) and220 mg Tablet D, Fasted (Ref-A2) based on Least Squares Mean oflog-transformed parameter values ^(b)Ratio(%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 14 Statistical Analysis of the Natural Log-Transformed SystemicExposure Dose-Normalized Parameters of Levetiracetam ComparingExtended-Release Tablet D, 220 mg under Fasted Conditions (Treatment A2)to Extended- Release Tablet A, 190 mg under Fasted Conditions (TreatmentA1) Dependent Geometric Mean^(a) Ratio (%)^(b) 90% CI^(c) ANOVA VariableTest Ref (Test/Ref) Lower Upper Power CV % ln(C_(max)/D) 0.0135 0.0119113.39 102.88 124.98 0.9825 21.58 ln(AUC_(last)/D) 0.2518 0.2371 106.2295.98 117.54 0.9754 22.49 ln(AUC_(inf)/D) 0.2579 0.2452 105.17 95.21116.16 0.9789 22.07 ^(a)Geometric Mean for 190 mg Tablet A, Fasted(Test-A2) and 220 mg Tablet D, Fasted (Ref-A1) based on Least SquaresMean of log-transformed parameter values ^(b)Ratio(%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 15 Statistical Analysis of the Natural Log-Transformed SystemicExposure Dose-Normalized Parameters of Levetiracetam ComparingExtended-Release Tablet D, 220 mg under Fed Conditions (Treatment B2) toExtended-Release Tablet D, 190 mg under Fed Conditions (Treatment B1)Dependent Geometric Mean^(a) Ratio (%)^(b) 90% CI^(c) ANOVA VariableTest Ref (Test/Ref) Lower Upper Power CV % ln(C_(max)/D) 0.0141 0.0130108.14 98.72 118.47 0.9906 20.41 ln(AUC_(last)/D) 0.2472 0.2404 102.8294.49 111.89 0.9959 18.87 ln(AUC_(inf)/D) 0.2534 0.2472 102.51 94.32111.42 0.9965 18.61 ^(a)Geometric Mean for 220 mg Tablet D, Fasted(Test-B2) and 220 mg Tablet D, Fasted (Ref-B1) based on Least SquaresMean of log-transformed parameter values ^(b)Ratio(%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

What is claimed:
 1. An extended release pharmaceutical compositioncomprising: a) 220 mg of levetiracetam; b) 280 mg-350 mg ofhydroxypropyl methylcellulose; c) 1.2 mg-1.4 mg of colloidal silicondioxide; d) 92.8 mg-119.2 mg of silicified microcrystalline cellulose;and e) 6.0 mg-6.7 mg of magnesium stearate.
 2. An extended releasepharmaceutical composition comprising: a) 220 mg of levetiracetam; b)280 mg of hydroxypropyl methylcellulose; c) 1.2 mg of colloidal silicondioxide; d) 92.8 mg of silicified microcrystalline cellulose; and e) 6.0mg of magnesium stearate.
 3. An extended release pharmaceuticalcomposition comprising: a) 220 mg of levetiracetam; b) 347.5 mg ofhydroxypropyl methylcellulose; c) 1.4 mg of colloidal silicon dioxide;d) 119.2 mg of silicified microcrystalline cellulose; and e) 6.7 mg ofmagnesium stearate.
 4. The pharmaceutical composition of any one ofclaims 1-3, wherein the hydroxypropyl methylcellulose is Methocel™ K15MCR or Methocel™ K100M Premium CR.
 5. The pharmaceutical composition ofany one of claims 1-3, wherein the hydroxypropyl methylcellulose isMethocel™ K15M CR.
 6. The pharmaceutical composition of any one ofclaims 1-5, wherein the silicified microcrystalline cellulose isProSolv™ HD90.
 7. An extended release pharmaceutical compositioncomprising: a) 190 mg of levetiracetam; b) 300 mg of hydroxypropylmethylcellulose; c) 1.2 mg of colloidal silicon dioxide; d) 102.8 mg ofsilicified microcrystalline cellulose; and e) 6 mg of magnesiumstearate.
 8. An extended release pharmaceutical composition comprising:a) 190 mg of levetiracetam; b) 300 mg of hydroxypropyl methylcellulose;c) 1.2 mg of colloidal silicon dioxide; d) 102.8 mg of anhydrousdicalcium phosphate; and e) 6 mg of magnesium stearate.
 9. Thepharmaceutical composition of claim 7 or 8, wherein the hydroxypropylmethylcellulose is Methocel™ K15M CR or Methocel™ K100M Premium CR. 10.The pharmaceutical composition of claim 7 or 8, wherein thehydroxypropyl methylcellulose is Methocel™ K15M CR.
 11. Thepharmaceutical composition of any one of claims 7, 9, and 10, whereinthe silicified microcrystalline cellulose is ProSolv™ HD90.
 12. Thepharmaceutical composition of any one of claims 1-11, wherein thecomposition is formulated for once daily administration.
 13. Thepharmaceutical composition of any one of claims 1-11, wherein thecomposition is formulated for one-unit-dosage-form-once-dailyadministration.
 14. The pharmaceutical composition of any one of claims1-13, wherein the composition is in the form of a tablet.
 15. Thepharmaceutical composition of claim 14, wherein the composition isformulated for one-tablet-once-daily administration.
 16. Thepharmaceutical composition of any one of claims 1-15, wherein thecomposition is formulated for oral administration.
 17. Thepharmaceutical composition of any one of claims 1-16, wherein thecomposition does not comprise a hydrophobic rate controlling polymer.18. The pharmaceutical composition of any one of claims 1-16, whereinthe composition does not comprise a functional coating.
 19. A method ofimproving cognition in a subject suffering from cognitive impairment orat risk thereof, wherein the method comprises administering thepharmaceutical composition of any one of claims 1-18.
 20. The method ofclaim 19, wherein the subject suffers from cognitive impairmentassociated with a central nervous system (CNS) disorder, or at riskthereof.
 21. The method of claim 19 or 20, wherein the cognitiveimpairment is associated with age-related cognitive impairment.
 22. Themethod of claim 21, wherein the age-related cognitive impairment is MildCognitive Impairment.
 23. The method of claim 22, wherein the MildCognitive Impairment is amnestic Mild Cognitive Impairment.
 24. Themethod of claim 19 or 20, wherein the cognitive impairment is associatedwith dementia, Alzheimer's disease, schizophrenia, amyotrophic lateralsclerosis, post traumatic stress disorder, cancer therapy, bipolardisorder mental retardation, Parkinson's disease, autism, compulsivebehavior, or substance addiction.
 25. A method of treating mildcognitive impairment due to Alzheimer's disease in a human subject inneed thereof, wherein the method comprises administering thepharmaceutical composition of any one of claims 1-18.
 26. A method oftreating amnestic mild cognitive impairment due to Alzheimer's diseasein a human subject in need thereof, wherein the method comprisesadministering the pharmaceutical composition of any one of claims 1-18.27. A method of slowing the progression of mild cognitive impairment dueto Alzheimer's disease in a human subject in need thereof, wherein themethod comprises administering the pharmaceutical composition of any oneof claims 1-18.
 28. A method of slowing the progression of amnestic mildcognitive impairment due to Alzheimer's disease in a human subject inneed thereof, wherein the method comprises administering thepharmaceutical composition of any one of claims 1-18.